In this study, we investigated the neural substrate involved in the comprehension of novel metaphoric sentences by comparing the findings to those obtained with literal and anomalous sentences using event-related functional magnetic resonance imaging (fMRI). Stimuli consisted of 63 copula sentences ("An A is a B") in Japanese with metaphorical, literal, or anomalous meanings. Thirteen normal participants read these sentences silently and responded as to whether or not they could understand the meaning of each sentence. When participants read metaphoric sentences in contrast to literal sentences, higher activation was seen in the left medial frontal cortex (MeFC: Brodmann's area (BA) 9/10), the left superior frontal cortex (SFC: BA 9), and the left inferior frontal cortex (IFC: BA 45). The opposite contrast (literal sentences in contrast to metaphoric sentences) gave higher activation in the precuneus (BA 7) and the right middle and SFC (BA 8/9). These findings suggest that metaphor comprehension is involved in specific neural mechanisms of semantic and pragmatic processing which differ from those in literal comprehension. Especially, our results suggest that activation in the left IFC reflects the semantic processing and that activation in the MeFC reflects the process of inference for metaphorical interpretation to establish semantic coherence.