Synovial sarcoma is characterized by a specific recurrent translocation t(X;18), resulting in either theSYT-SSX1orSYT-SSX2gene fusion. Because this is the primary genetic alteration in these tumors, we sought to identify the impact of molecular heterogeneity of the t(X;18) on cell proliferation, apoptosis, and epithelial differentiation in synovial sarcoma. Seventy-three patients with synovial sarcoma (18 biphasic, 55 monophasic) were selected on the basis of availability of tumor material for molecular and immunohistochemical analysis. Tumors were classified as biphasic on the basis of morphologic glandular differentiation.SYT-SSXfusion transcripts were examined by reverse transcriptase polymerase chain reaction using tumor RNA extracted from frozen or paraffin-embedded tissue. Cell proliferation was assessed immunohistochemically by the Ki-67 labeling index. Apoptosis was analyzed immunohistochemically with BAX and BCL2 antibodies and by the TUNEL method. Immunohistochemical evidence of epithelial differentiation was assessed using antibodies to cytokeratins and epithelial membrane antigen. Approximately two thirds of the tumors had anSYT-SSX1and one third had anSYT-SSX2fusion transcript. There was a strong association betweenSYT-SSXfusion type and histologic subtype. All biphasic synovial sarcomas had theSYT-SSX1fusion, whereas all tumors withSYT-SSX2were of monophasic morphology. There was, however, no association betweenSYT-SSXfusion type and expression of cytokeratins and epithelial membrane antigen among monophasic tumors. Tumors withSYT-SSX2had a significantly higher mean and median Ki-67 labeling index than those withSYT-SSX1, but a comparison of Ki-67 according to fusion type, histologic type, and sample source suggested that the main determinants of proliferation rate were the latter two factors. Specifically, monophasic tumors and metastatic tumors showed significantly higher Ki-67 scores. Apoptosis (by TUNEL) was rarely observed, consistent with prominent expression of the anti-apoptotic protein BCL2 in almost all cases. TUNEL, BCL2, and BAX results did not correlate withSYT-SSXfusion type. These data confirm the strong association ofSYT-SSXfusion transcript type with morphologic but not immunophenotypic epithelial differentiation in synovial sarcoma.