Failure of apoptosis is one of the hallmarks of cancer. As an execution-phase caspase, caspase-6 plays a crucial role during apoptosis. To explore the possibility that the genetic alterations of CASP, which encodes caspase-6, might be involved in the development of human cancers, we analyzed the entire coding region and all splice sites of the human CASP6 gene for the detection of somatic mutations in 100 colorectal carcinomas and 50 gastric carcinomas. Overall, we detected three somatic mutations of the CASP6 gene, including two missense mutations and one splice-site mutation. The mutations were observed in two of the 100 colorectal carcinomas (2.0%) and one of the 50 gastric carcinomas (2.0%). Of note, one colorectal carcinoma with the CASP6 mutation harbored CASP3 and CASP8 gene mutations as well. We also analyzed caspase-6 expression by immunohistochemistry, and found that caspase-6 was expressed in 60% of the gastric cancers and 90% of the colorectal cancers. This is the first report on CASP6 gene mutations in human cancers, and these data indicate that the CASP6 gene is occasionally mutated in gastric and colorectal carcinomas. Also, the data suggest the possibility that deficiency of caspase-6 expression might contribute to the pathogenesis of gastric cancers.