Tuscany by Rental Car - logistics of pick up/drop off?

I would consider 2 possibilities ...

Oct 22 - Train from Venice to Siena (2 nights). Rental car for 2 days to see Tuscan countryside.
Oct 24 - Train from Siena to Florence (2 nights)
Oct 26 - Train to Rome

Oct 22 - Train from Venice to Florence (2 nights).
Oct 24 - Pick up rental car in Florence, Chianti drive, San Gimignano, then to Siena (1 nt)
Oct 25 - Drive to Montepulciano, then to Orvieto (1 nt)
Oct 26 - Return rental car in Orvieto, then train to Rome

I have no experience with cars in Tuscany (nor anywhere else, I must say), but I would advise to look for a medium-sized city like Spoleto, where you have car rentals, hotels with parking spaces, rail connections (from Venice and to Rome), and a choice of restaurants at walking distance from your hotel.
It can be my European perspective, but all our Tuscan time is just four nights.

djp_syd: Thanks for your thoughts. What do you think of not spending any time in Siena or Florence? Obviously a personal choice, but we will already be doing Venice and Rome, and really like the idea of contrasting those urban adventures with driving through the countryside and getting off the beaten track as much as possible with a rental. It also raises where we met set up base and do day trips for the 4/5 days.

You don't have to stay in Sienna, just pick up the car there and drive to a agriturismo in the region

If when in Tuscany you plan to stay in a small village or out in the countryside in an Agriturismo/villa/whatever, you will need a car. And if need a car, in my opinion, it only makes sense to rent right from Venice and comfortably drive the 3 hours (all on freeways) down to Tuscany. Doing so will spare you having to drag your luggage on the train, off the train, to the rental agency (which is quite a walk from the station both in Florence or Siena). It will also save you the train fare (which is more than you need in fuel and tolls if it's 2 or more people traveling together).

The drive from Venice to Siena area, for example, is about 3 hours all on very nice freeways. From Venice Piazzale Roma (where all rental pick up will be) just cross the bridge into Mestre and follow the green signs saying AUTOSTRADE. Get on the freeway (when you go through the toll booths pick up your ticket) and follow directions to (in this order) PADOVA, BOLOGNA, FIRENZE. Once near FIRENZE (Florence) keep an eye for the FIRENZE IMPRUNETA exit and then there, after paying toll, continue on to Siena on the Raccordo (another divided 4 lane highway which is however toll free).

The car rental return can be in Rome. Select a drop off near the Tiburtina station which is easy to reach from the TANGENZIALE EST/A24 freeway. If you rent from Hertz you could also return it in Orvieto and proceed by train from there. If Orvieto is part of your itinerary, that would be an option.

Here is another idea, although there is nothing wrong with djp_syd or your idea of bypassing Siena and Florence.

Rent a car in Venice on the 22nd (either at the Piazzale Roma or the airport). Drive to Bologna, spend the night, have some good food. The Marriott (AC Hotel) has parking and is close to the autostrada for departure the 23rd. If you have time see Padua or Ferrara on the way to Bologna.

Drive to San Gimignano, Volterra, or Pienza in Tuscany, or, Panzano in Chianti and see Dario Checchini the butcher (Google him). You will have to find a place to stay that fits these locations. Maybe the wine towns of Montalcino or Montepulciano. You could even go over to Lucca, spend a night then drive down through the Tuscan countryside to other towns.

Then to Orvieto to drop the car and train to Rome. I suggest you don't fuss with driving in Rome.

I presume you already know what towns you want to visit in Tuscany, so I'll add my agreement with those above who say pick up your rental car in Venice. It's easy. Then plan a place to drop it on the ring road around Roma. I did this in the reverse and it worked out well. We took a cab from our hotel in Roma to the car rental place on the ring road, got in our car and right onto the Autostrada, avoiding driving in the city. I'm sure you could get a cab or ask them to call one for you at the rental car place to take you into the centro or wherever you're staying.

Second Roberto's plan... that is what I was going to suggest as I have done this same thing. It is such a hassle to take a train somewhere just to get a car... just pick it up on your way out of Venice. No need to add another city to a trip if you want the countryside... I could spend months in the villages of Tuscany and never bother with any big cities, but that is what I love, so you have to do what makes you happy.
I did find driving in Siena to be a pain... Congestion and little parking, so I usually don't stay there with my car. The other thing I did on one trip was to drop the car in Florence at the airport and took the train to Rome. I spent last night in Florence so I was rid of the car the day before, but I have also dropped it in Rome or Orvieto... whatever fits your itinerary.

Siena is a province as well as a city. Choose your out of town accommodation carefully to give you maximum options. Parking of course is a must, but check for local public transport options if you want to get in to the centre of Siena or Florence.

Oct 22 - Train from Venice to Lucca (1 night)
Oct 23 - Pick up rental car in Lucca, drive to Volterra/San Gimignano, then to accomm near Siena (2 nights)
Oct 24 - Day spent in either Siena or Florence (by public bus), or drive through Chianti countryside
Oct 25 - Drive to Montepulciano, then to Orvieto (1 nt)
Oct 26 - Return rental car in Orvieto, then train to Rome

Thanks so much for all the thoughtful replies! I've booked a car from Venice (Piazzala Roma) to a Rome location just inside the ring road (Via Salario 1300). Roberto, thanks in particular for the detailed directions out of Venice.

If anyone has recommendations on accommodation that would be much appreciated, as we haven't booked anything yet. Again, we'll not be staying at larger centres (ie Florence, Siena), as we want to see countryside and relaxed, smaller communities.

Just make sure you've got good insurance, money for tolls, and lots of money for Petrol. Learn how to operate all necessary features BEFORE you leave the car rental facilities.

http://www.agriturismo.it/en/

If you want to drive to Siena through the famous Chianti Road (SR 222), exit the A1 toll freeway one exit after Firenze Impruneta. The exit (the last one in Florence) is called FIRENZE SUD. As soon as you pay toll, turn right 50 mts after the toll booths, toward the Sheraton Hotel (you will see it on your right from the toll booths). Just follow the blue signs to SIENA SR 222. The Chianti Rd is a curvy 2 lane highway so it takes longer to get to Siena (almost 2 hours plus pit stops to imbibe at the wineries), but it's a classic beautiful drive.