Female C57BL/6 mice were exposed for 6 h/day, 5 day/wk for 2 weeks, to 1,500 ppm methyl chloride. Focal and diffuse malacia, involving the cerebellar inner granular layer was found while renal lesions were minimal or absent. The cerebellar lesions were most frequently found in the ventral paraflocculus, and less often in other regions of the cerebellum. The earliest ultrastructural changes were seen in the nuclei of scattered cerebellar granule cells, with progression from slight confluence of heterochromatin, to complete nuclear condensation or karyorrhexis. More severely affected areas exhibited severe watery swelling and disruption of granule cell perikarya with less severe changes in other cell types. Blood vessels appeared normal, even in areas of severe malacia. It was concluded that the lesions in the mouse cerebellum closely resemble methyl chloride induced brain lesions previously described in guinea pigs, and that these lesions are not secondary to the renal toxicity of methyl chloride.