Substantial evidence indicates that the characteristic SS18-SSX fusion gene may play an important role in synovial sarcoma development and progression. For obtaining better insights into the genetic alterations and molecular mechanisms involved in synovial sarcomas and for developing novel therapeutic strategies for this disease, we first examined the efficiency of small interfering RNAs (siRNAs) targeting the SS18-SSX1 fusion gene in knocking down its expression in the human synovial sarcoma cell line HS-SY-II, and then evaluated the effects of downregulation of this gene on apoptosis, apoptosis-related gene expression, growth regulatory proteins, and the growth of tumor cells in vitro. We observed a marked decrease (by more than 87.6%) in SS18-SSX1 expression levels in cells transfected with a plasmid expressing hairpin siRNA for this gene, which was accompanied by (i) reduction in protein levels of cyclin D1 and cyclin A, (ii) reduction in antiapoptotic protein Bcl-2 and activation of caspase 3/apoptosis, and (iii) growth inhibition of HS-SY-II cells in vitro. Our results demonstrate that siRNA targeting of SS18-SSX1 may have therapeutic potential in the treatment of synovial sarcomas.