2012: updating as it's still receiving very good reviews
This hotel came as part of an air/hotel package and while I was initially a little concerned about distance from many of the main historic sites, it worked out perfectly. Hotel Giulio Cesare is in a 1916-era villa just across the Tiber from Piazza Del Popolo and Villa Borghese. Classic rooms are small (as they are in most Roman hotels) and have very high ceilings but are clean, quiet, have comfortable beds, and you won't be in one much anyway, right? Superior grade and quadruples are available if needing more room. It has most of the amenities you'd expect from a European 4-star (TV, safe, AC, elevator, wifi, hairdryers) except for a restaurant but you can get good snacks and drinks in the bar or lovely garden. Clean, safe neighborhood with a residential feel and probably quieter than more popular parts of the centro storico.
It's about 15 minutes on foot to the Spanish Steps or the Vatican, and we found the 1-mile or so distance to the Forum, Colosseum, etc. a great walk as there's so much to see along the way. There is a Metro station very close to the hotel but we never used it: had too much fun wearing out our sneakers!
Not quoting prices here as they can swing a lot depending on season and special events. One word of caution: reviews have not been as favorable for economy rooms in the questhouse.
Unique Quality: Loved it for the excellent breakfast (included) and wonderful garden next to the bar. The walled garden was large and gently lit after dark; perfect for that last nightcap before calling it a day. Breakfast was the best we had on our 2007 Italy trip and still one of the raves from more recent guests. Hotel personnel - especially bar and breakfast staff - were terrific.
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Address: Via Degli Scipioni 287, Rome, Lazio, 00192, Italy