We investigated the influence of sentence context on initial integration of novel word meanings into semantic memory. Adults read strongly or weakly constrained sentences ending in known and unknown (novel) words as electrical brain activity was recorded. Word knowledge was assessed via a lexical decision task where recently seen known and unknown word sentence endings served as primes for related, unrelated, and synonym/identical target words. N400 amplitudes to target words preceded by known word primes were reduced by prime relatedness. Critically, N400 amplitudes to targets preceded by novel words also varied with prime relatedness, but only if they initially appeared in highly constraining sentences. These results demonstrate that electrical brain activity accompanying one-shot contextual word learning is modulated by contextual constraint and reveals a rapid neural process that can integrate information about word meanings into the mental lexicon.