Clear cell sarcoma (CCS) is a rare soft tissue sarcoma with morphological similarities to malignant melanoma (MM), but with a distinct genetic background that includes the chromosomal translocation t(12;22)(q13;q12). Clear cell sarcoma is often misdiagnosed as MM because of similarities in target locations and immunophenotypes. Eighteen cases with MM in non-cutaneous sites were subjected to fluorescence in situ hybridization (FISH) to assess EWS gene breakage. Tissue microarrays were constructed using formalin-fixed, paraffin-embedded tissue and the EWSR1 (22q12) dual-color, break-apart rearrangement probe (Vysis) was used. Two patients were classified as CCS with EWS gene rearrangement, with a mean of 67.5% positive cells per sample according to break-apart FISH. The remaining 16 patients lacked break-apart signals of the EWS gene. The presence of type 1 (EWS exon 8-ATF1 exon 4) fusion transcripts was confirmed in FISH-positive patients by RT-PCR. Retrospective analysis revealed that the masses were located in the foot and buttock, respectively. Morphologically, tumor cells were not typical for those of CCS or MM. Break-apart FISH is an accurate and convenient method for differentiating between MM and CCS. Molecular detection of EWS gene rearrangement, either by break-apart FISH or RT-PCR, is mandatory in subjects with melanotic tumors of soft tissue.