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), 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.