Linguistic theories distinguish between syntax (sentence form) and semantics (sentence meaning). Correspondingly, recent studies have shown that syntactic and semantic anomalies elicit distinct changes in the event-related brain potential (ERP). However, these results have been obtained with highly artificial methodologies and have not yet been generalized to more natural reading conditions. Here, we recorded ERPs while subjects read a naturalistic prose passage. The subjects either read for comprehension with no other task being assigned or read for comprehension and made acceptability judgments after each sentence. Consistent with prior work and regardless of the subjects’ assigned task, syntactic anomalies elicited a large positive wave (P600), whereas semantic anomalies elicited a large increase in N400 amplitude. These results demonstrate that the qualitatively distinct ERP responses elicited by syntactic and semantic anomalies are not artifacts of unnatural aspects of previously used stimuli, thereby providing additional evidence that separable syntactic and semantic processes exist.