Repetition priming has been characterized neurophysiologically as a decreased response following stimulus repetition. The present study used event-related functional magnetic resonance imaging to investigate whether this repetition-related response is sensitive to stimulus familiarity. A right fusiform region exhibited an attenuated response to the repetition of familiar stimuli, both faces and symbols, but exhibited an enhanced response to the repetition of unfamiliar stimuli. Moreover, both repetition effects were modulated by lag between successive presentations. Further experiments replicated the interactions between repetition, familiarity, and lag and demonstrated the persistence of these effects over multiple repetitions. Priming-related responses are therefore not unitary but depend on the presence or absence of preexisting stimulus representations.