We used event-related fMRI (ER-fMRI) to test the hypothesis that metaphors bias cognitive processing of semantic relatedness towards a search for a wider range of associations. Twelve right-handed male volunteers read a mixture of metaphoric and literal sentences, each sentence being followed by a single word, which could be semantically related or not to the preceding sentence context. We found that judging unrelated words as contextually irrelevant was associated with increased blood oxygenation level-dependent (BOLD) signal in the right ventrolateral prefrontal cortex in the metaphoric but not in the literal condition. The same region was also activated when subjects endorsed a semantic relation between words and metaphoric sentence primes but not between words and literal sentence primes. We argue that these results are consistent with the notion of semantic open-endedness, whereby figurative statements bias cognitive processing towards a search for a wider range of semantic relationships compared to literal statements, and thus lend further support to the view that coarse semantic coding occurs preferentially in the right hemisphere.