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ABSTRACT: One important issue in neuroimaging research on language is how the brain processes and represents lexical semantics. Past studies with various paradigms reveal that the left inferior prefrontal and mid-superior temporal regions play a crucial role in semantic processing. Those studies, however, typically utilize words having a precise and dominant meaning as stimuli and have not manipulated lexico-semantic ambiguity, a key feature of human language, as an experimental variable. Here, we used a word generation paradigm to examine whether neuroanatomical networks for meaning are modulated by lexical ambiguity. We found that, compared with semantically precise words, semantically ambiguous words were mediated by strong brain activations in the left dorsal–lateral frontal areas, the anterior cingulate, and the right inferior parietal lobe. Semantically precise words, instead, were associated with the left inferior prefrontal and mid-superior temporal sites. These findings indicate that semantic analysis of written words is a dynamic process involving coordination of widely distributed neural subsystems, which are weighted by semantic ambiguity.