Amplification and/or overexpression of HER2/neu have been documented in many types of epithelial tumor and recently has been reported in sarcomas, particularly in osteosarcomas. But the role of HER2/neu alterations in soft tissue tumors remains poorly understood. Thus the present study investigates the expression of HER2/neu in 13 patients with synovial sarcoma (SS). In this study, HER2/neu mRNA levels were measured in frozen tissue samples using a real-time reverse transcription-polymerase chain reaction assay; protein expression was assessed by immunohistochemistry using an anti-HER2/neu polyclonal antibody. Six normal skeletal muscle specimens were used to establish basal levels of HER2/neu mRNA. HER2/neu transcripts were detected in all normal tissues and SSs. Four of 13 sarcomas (31%) demonstrated HER2/neu mRNA levels above the mean value, whereas 3 tumors (23%) displayed HER2/neu protein overexpression. Both membranous and cytoplasmic patterns of immunostaining were observed, and a strong correlation was found between protein expression and mRNA level (P = 0.01). Increased HER2/neu mRNA levels were significantly associated with a lower risk of developing recurrences (P = 0.02). Moreover, none of the patients with HER2/neu overexpression developed metastasis. Our data demonstrate that HER2/neu is expressed in SSs and that both membrane and cytoplasmic HER2/neu expression correlate with mRNA levels. Our results show that the presence of increased levels of HER2/neu in SSs is associated with a more favorable clinical course. Further studies are needed to assess the role of this oncogene in SSs and to evaluate the application of inhibitory humanized monoclonal antibodies in the treatment regimens for this malignancy.