With strong and valid predictions, grasping a message is easy, whereas more demanding processing is required in the absence of robust expectations. We here demonstrate that brain correlates of the interplay between prediction and perception mechanisms in the understanding of meaningful sentences. Sentence fragments that strongly predict subsequent words induced anticipatory brain activity preceding the expected words; this potential was absent if context did not strongly predict subsequent words. Subjective reports of certainty about upcoming words and objective corpus-based measures correlated with the size of the anticipatory signal, thus establishing its status as a semantic prediction potential (SPP). Crucially, there was an inverse correlation between the SPP and the N400 brain response. The main cortical generators of SPP and N400 were found in inferior prefrontal cortex and posterior temporal cortex, respectively. Interestingly, sentence meaning was reflected by both measures, with additional category-specific sources of SPPs and N400s falling into parieto-temporo-occipital (visual) and frontocentral (sensorimotor) areas for animal- and tool-related words, respectively. These results show that the well-known brain index of semantic comprehension, N400, has an antecedent with different brain localization but similar semantic discriminatory function. We discuss whether N400 dynamics may causally depend on mechanisms underlying SPP size and sources.