Driving in Tuscany - pick car from Rome or from Chiusi?

Take a 70 minute train ride from Rome Termini to Orvieto--a very popular Umbrian hilltown.
The Hertz agency is across the street from the train station parking lot.
It's a very, very popular pickup and drop off location for those coming and going from Rome.
The 4 lane toll/controlled access highway is there running north and south--making travel quick and efficient.

Thanks a lot David.

I checked google map and looks like if we leave Rome in the morning, the only train available is the slow one and will need about 2 hour to arrive Orvieto?

I'm not sure where you're checking, but the Trenitalia website shows 2 morning trains departing Roma Termini for Orvieto and Chiusi and a late morming train departing from Roma Tiburtina. For example, you can depart Roma Termini at 9:00 and arrive in Orvieto at 10:14 or Chiusi at 10:40 (same train). You may need to click on the Regionali tab to get these solutions. Either Orvieto or Chiusi would be a good pick-up point for a rental car.

Let's say you are in Philly and need to go to Washington DC. Do you take the train to Baltimore, rent a car in Baltimore, then drive the last 50 miles from there? Or do you rent the car in Philly and drive all the way from Philly to Baltimore?

If you'd do the latter, then why is Rome so different? Rent a car on Via Sardegna (both Europcar and Hertz are there) which is even walking distance from the Spanish steps, then drive straight the Via Pinciana to the via Salaria all the way to the A1 freeway.

No major traffic if you leave between 10 and noon in the morning. Traffic will be heavy if you leave Rome during the evening commute.

Well, they don't have ZTL's in Baltimore or Washington. Perhaps the answer depends on whether the OP lives-to-drive, or drives-to-travel? We stopped in Viterbo and Orvieto on the way farther north, but we started at Civitavecchia, avoiding any urban unpleasantness in Rome. A big plus of the train is both people get to look out the window, and start fresh after a sweet walk around and a lunch in Orvieto. Appeals to me!

We have taken the train from Rome to Chiusi to pick up a rental car for driving to Montepulciano, and it worked well for us. (Though this was 10 years ago?) We have also dropped off a car in Orvieto, and that worked well too. In both towns, the Hertz office is right next door to the train station. Chiusi is a bit smaller than Orvieto, which can be good (not as busy and more personal service) or bad (possibly open fewer hours).
Like you, we didn't really want to drive in Rome. The train trip was much more relaxing than trying to drive. You can definitely do it that way if you want to.
Have fun!!

I agree with David. We just did the drop off at Hertz in Orvieto and we couldn't have picked a better location if we had planned it.