Cancers of the microsatellite mutator phenotype (MMP) show exaggerated genomic instability at simple repeat sequences. More than 50 percent (21 out of 41) of human MMP⁺ colon adenocarcinomas examined were found to have frameshift mutations in a tract of eight deoxyguanosines [(G)₈] within BAX, a gene that promotes apoptosis. These mutations were absent in MMP⁻ tumors and were significantly less frequent in (G)₈ repeats from other genes. Frameshift mutations were present in both BAX alleles in some MMP⁺ colon tumor cell lines and in primary tumors. These results suggest that inactivating BAX mutations are selected for during the progression of colorectal MMP⁺ tumors and that the wild-type BAX gene plays a suppressor role in a p53-independent pathway for colorectal carcinogenesis.