Pantomime of tool use is a frequently used test for apraxia. For basic cognitive neuroscience, pantomime of tool use is of interest because it constitutes a link between instrumental and communicative manual actions. We used lesion subtraction analysis to determine the locations specifically associated with defective pantomime of tool use in patients with left-brain damage and aphasia. Subtraction of lesions of patients with normal pantomime from those with defective pantomime yielded a maximum difference in the inferior frontal gyrus and adjacent portions of the insula and precentral gyrus. This result remained essentially the same when possible confounding influences of impaired language comprehension and of lesion size were controlled by selecting patients equated on these measures and when only patients with preserved imitation of gestures were considered. By contrast, parietal lesions did not have a specific impact on pantomime. We speculate that the vulnerability of pantomime to lesions of left inferior frontal cortex is due to the high demands on selection of a very restrained range of features out of the many features that may come to mind when imagining the actual use of the tool.