Very little research has explored which neural systems may be important for retrieving the meanings of locative prepositions (e.g., in, on, around). To begin to address this knowledge gap, we conducted a lesion study in which we tested the hypothesis that processing the meanings of locative prepositions depends on neural structures in the left inferior prefrontal cortex and left inferior parietal cortex. Seventy-eight subjects with focal, stable lesions to various parts of the telencephalon and a comparison group of 60 normal participants were studied with tasks that require production, comprehension, and semantic analysis of locative prepositions. In support of our hypothesis, we found that in subjects with impaired knowledge of locative prepositions, the highest region of lesion overlap was in the left frontal operculum and the left supramarginal gyrus, and in the white matter subjacent to these two areas. In a second study, focused on six subjects who had pervasive defects for locative preposition knowledge, we confirmed that such defects were associated specifically with damage to the posterior left frontal operculum, white matter subjacent to this region, and white matter underneath the inferior parietal operculum. These subjects did not have basic impairments in spatial processing or working memory, and they had relatively well-preserved processing of conceptual knowledge for actions and various categories of concrete entities (e.g., persons, animals, tools). All six subjects, however, had defects in naming actions, and some of them also had defective naming of some categories of concrete entities. Overall, the findings converge nicely with recent results from functional imaging approaches, and with classic studies from the aphasia-based literature, and suggest that the left inferior prefrontal and left inferior parietal regions have crucial-albeit not exclusive-roles in processing knowledge associated with locative prepositions.