Previous electrophysiological and neuroimaging studies suggest that the mismatch negativity (MMN) is generated by a temporofrontal network subserving preattentive auditory change detection. In two experiments we employed event-related brain potentials (ERP) and event-related functional magnetic resonance imaging (fMRI) to examine neural and hemodynamic activity related to deviance processing, using three types of deviant tones (small, medium, and large) in both a pitch and a space condition. In the pitch condition, hemodynamic activity in the right superior temporal gyrus (STG) increased as a function of deviance. Comparisons between small and medium and between small and large deviants revealed right prefrontal activation in the inferior frontal gyrus (IFG; BA 44/45) and middle frontal gyrus (MFG; BA 46), whereas large relative to medium deviants led to left and right IFG (BA 44/45) activation. In the ERP experiment the amplitude of the early MMN (90-120 ms) increased as a function of deviance, by this paralleling the right STG activation in the fMRI experiment. A U-shaped relationship between MMN amplitude and the degree of deviance was observed in a late time window (140-170 ms) resembling the right IFG activation pattern. In a subsequent source analysis constrained by fMRI activation foci, early and late MMN activity could be modeled by dipoles placed in the STG and IFG, respectively. In the spatial condition no reliable hemodynamic activation could be observed. The MMN amplitude was substantially smaller than in the pitch condition for all three spatial deviants in the ERP experiment. In contrast to the pitch condition it increased as a function of deviance in the early and in the late time window. We argue that the right IFG mediates auditory deviance detection in case of low discriminability between a sensory memory trace and auditory input. This prefrontal mechanism might be part of top-down modulation of the deviance detection system in the STG.