Clear cell sarcoma (CCS) is a rare tumor classically associated with the tendons and aponeuroses of distal extremities of young adults. CCS and malignant melanoma (MM) share immunohistochemical profiles and ultrastructural features, but classic CCS has characteristic morphology with low mitotic activity and minimal pleomorphism. Occasional cases show pleomorphism, high mitotic index, and/or melanin pigmentation, making CCS indistinguishable from MM based on morphology. However, CCS is genetically distinct owing to its consistent association with a t(12;22)(q13;q12) chromosomal translocation, leading to the formation of the EWS/ATF1 fusion transcript. This translocation has never been documented in cutaneous melanoma, and thus is regarded as specific for CCS. Recent evidence suggests that primary "malignant melanomas" in unusual anatomic sites, most notably the gastrointestinal (GI) tract, may be CCS. This is supported by 11 cases of primary GI CCS with the t(12;22) translocation. We used reverse-transcription polymerase chain reaction and fluorescence in situ hybridization to examine whether a proportion of cases diagnosed as MM of the GI tract in patients without a history of cutaneous MM actually represent primary GI CCS. In total, we examined 7 cases: Four with no prior history of MM, 2 with histories of cutaneous MM, and 1 with an anal MM. All 4 cases for which there was no history of cutaneous/mucosal MM harbored the EWS/ATF1 fusion transcript. We report the largest series of GI CCS and have shown that molecular studies may be warranted in cases that otherwise seem to represent MM of unusual primary locations.