I'd have to echo libertyjake's review of the Hilton Prague.
I, too, am a Starwood whore. My few experiences with Hiltons in the US have been less than overwhelming, though I've been to some nice Hilton properties outside of the US (seems similar to Sheraton in the sense that things can be somewhat hit or miss in the US, but often kicked up a notch outside of the US).
But the Prague Hilton was tremendous. Before arrival, I was a bit concerned it was too much of a business-oriented hotel (read: little atmosphere) but I was quite off. Amenities, service, rooms were all great.
Location was not a problem in the least, either. Certainly, you don't quite step out the front door of the hotel and land on the most charming, picturesque scene in Prague. But it's not hard to get to the most popular tourist spots from the hotel, the car service they offer is very convenient (and, with flat prices, reasonable and reliable), the views from the upper floors can be spectacular, and the extent to which you're able to enjoy the hotel and its facilities makes it a very appealing "retreat" after a long day of sightseeing or business meetings offsite.
Highly recommended!