We report on the cytogenetic and molecular analysis of a malignant melanoma of the soft parts (MMSP). A t (12; 22)(q13; q12) was found as the only structural chromosomal change, and this provides additional support for the important role of this translocation in MMSP development. Molecular analysis revealed in frame fusion between exon 10 of the Ewing's sarcoma oncogene (EWS) and codon 110 of ATF-1. In previously analyzed MMSPs, junctions were observed between EWS exon 8 and ATF-1 codon 65. The present data thus indicate that, as in Ewing's sarcoma, different fusion proteins can occur in MMSP. The presence of the EWS/ATF-1 fusion gene in the tumor cells was demonstrated by dual color fluorescence in situ hybridization on interphase nuclei. Our data provide additional support for the specific association of the t (12; 22) and the resulting EWS/ATF-1 gene fusion in MMSP. This particular genetic aberration, therefore, serves as a strong diagnostic marker for MMSP. We conclude that detection of the t (12; 22) by cytogenetic or molecular analysis is useful in establishing or confirming the diagnosis of MMSP.