I haven't rented a car in Rome, but I've driven there. Generally, the outskirts towards the ring road are easy enough to get in and out of by car. So if you're not packing too much stuff and want to minimize headaches, I'd just rent a car somewhere that's easy to access from the metro.
So places like EUR or out towards Cinecitta are 15-20 minute train rides from the center of the city and you can usually end up a few hundred meters from a car rental place. Then from there, it's usually only about 5 minutes drive to the freeway.
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