Italy in May - itinerary help, please

I'll try to answer in the same order.

Day 1 It's a 2-hour train ride from Orvieto to Rome, then you have to get to your hotel. It's probably going to be cheaper to pay for parking in Rome than the round-trip train tickets.

Days 3-5 I'd probably choose 2 nights in Orvieto and one in Assisi. There's more to see in Orvieto (IMO) and more restaurants to choose from.

Days 6-9 Do you know about the ZTL in Italy? If you inadvertently drive into one of these zones, you will be spotted by a camera and get hit with a hefty fine. I don't know about Assisi, but the centers of Siena and Florence are off-limits to non-residents. You're probably better off staying in one and taking the bus (1 hour ride) from center to center. Or stay at an agriturismo for your time in Tuscany.

Days 10-11 Since Venice is "non-negotiable" you'll have to cut something from the days before. You need 2 full days there to make it worthwhile. And as you noted, it's a long way to drive from Tuscany and much longer from there to the CT. If your friends haven't bought their flights yet, or can change them, it would make the most sense to fly into Venice and start there.

CT You may want to stay where it's most convenient to get your friends to the Genoa airport at 5-6 a.m. Every town has its charms.

I like Chani's suggestions, but if you don't want to go to Venice and your friends do, perhaps if they haven't bought tickets yet they could end their trip in Venice without you.

About driving: I travel in Italy every summer, and for a couple of weeks two friends from Switzerland meet up with me. We rent a car, rather than use theirs.

First, this itinerary is way too hectic for my personal taste. That said, don't get hung up on the technical location of your destinations. Yes, Tuscany is lovely (as you'll see in Siena), but if it's beauty they want, they'll get plenty of that from the gorgeous hilltop towns of Orvieto and Assisi, both of which are in Umbria (though Orvieto just barely - you can see Tuscany from it).

Every place on your initial list is served by train. To me, the benefit of having the car would be to include more towns that are not served by train, such as Gubbio vs. Assisi; and many Tuscan hill towns.

If you have your own car, which is "free," then I would keep it and park as close to your destinations as possible, including at Venice. Car fits all four of you, allows you to be on your own schedule, and becomes your "home" on the road, a point of consistency in the trip. Car is not without costs (autostade tolls from Florence to Venice about €40 per www.viamichelin.com, more for gas, €20/day for parking at Tronchetto) but neither is train (regular 2nd-class fare from Florence to Venice about €40 per person, one way, unless you lock in timing months ahead).

If you were not planning to drive everywhere, then maybe you would fly to/from Brussels; see www.skyscanner.com.

As was mentioned, maybe Orvieto 2 nights rather than Assisi. We loved B and B Ripa Medici, which has parking included or maybe 5 Euros per night. An apartment and another with 2 rooms each with their own bath and a shared living room and kitchen. I believe it was 80 Euros per night per room. Book early.

We were underwhelmed with Siena. I would vote for more time in Florence with day trips to Siena and other parts of Tuscany. Not sure what to do about your car while in Florence.

My first thought was that it was far too hectic- too many locations for a 2 week trip. Just looks like a lot of travel/drive time- not much exploring/savoring time to me. And technically only 11 nights since you are committed to CT on Day 12.

We just did 17 nights- 3 Venice-3 Florence- 5 Rome with 6 nights in between with a car for 2 Siena, 2 Montepulciano and 2 Assisi.
When you only have 2 nights in a town- that is really just 1 full day by the time you deal with arrival, parking, checking in, checking out, etc.
We loved all 3 cities equally so I would not know how to cut one of those out! although Venice is the outlier in your case.
Our favorite small towns were Montepulciano and Assisi- we skipped Orvieto- it just would not fit and we tried very hard to avoid 1 night stays.
One night in Siena would have been enough - wished we had done 4 in Florence instead and day tripped to Siena- I guess we were underwhelmed by Siena too- but we did think the Duomo there was fabulous.
Since you plan to travel with car I might weigh the ease of getting to/into/parking at the places on your list- and eliminate those that will be most difficult.

First time in Italy and almost no time in Rome? Spend at least a couple of nights there (3 nights would be my recommendation).
Find a hotel in Rome that has parking arrangements. There are plenty outside the historical center.
You can visit Orvieto in just a few hours, so you could actually visit it from Rome (by train or car) without changing hotels.
You can stay two nights in Assisi, but Assisi itself can be visited in a few hours. But I guess you can also visit Gubbio, Spello, Perugia, etc.
I wouldn't split nights between Siena and Florence. Just choose one and visit the other from there. They are only 45 min apart by car (although once at night I made it in less than 30 minutes, but that was before speed radars were used and I was too young and stupid). Both have traffic restrictions in the city center, so choose a hotel outside the restricted zone (with Parking) or simply stay in some small village or in the countryside in between the two cities.

For Venice you should drive, since you have a free car and several people and Cinque Terre later. You might consider staying in Mestre. Not as pretty but a quick train ride to Venice and many hotels in Mestre have parking arrangements (try Hotel Tritone at the Mestre station). Parking in Venice will be at Piazza Roma or Tronchetto island, therefore far from your Venice hotel and they charge 25euro + a day to park there.
For the Cinque Terre stay in Monterosso. More car friendly and more hotels/restaurants. Also closer and faster to Genoa.
For lakes, You could do either Lake Maggiore or the Como branch of lake Como. For Maggiore stay in Stresa. For lake Como stay in Menaggio. From there you can easily go to Lugano and proceed north to Belgium.