Tricky one.
I'm going to say Okami, because that's the first that comes to mind. I think I could come up eith more creative titels though, if I think long and hard on it.
I also think that Nintendo has the most creative games. They rehash much of their big IP's, but when these titles were new they set the creative standard, something which they repeated with the transition to 3D gaming (without the glasses :P, talking about OoT and Mario 64 for instance). More recently, Pikmin serves as an example of (a) great game(s) doing really creative things.
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