The prognosis of patients with synovial sarcomas is poor. New therapeutic strategies, such as target inhibition of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) with erlotinib and gefinitib, could be effective, because most synovial sarcomas overexpress this protein. In lung cancer, the responsiveness to gefinitib is strongly related to the presence of mutations in the tyrosine kinase domain of the EGFR gene, while erlotinib sensitivity seems to be partly linked to chromosome 7 polysomy or gene amplification. To clarify the role of EGFR in synovial sarcoma and to explore the potential for a targeted therapy approach, we have examined 13 of these soft tissue tumors. We have analyzed the EGFR expression by immunohistochemistry, searched for polysomy and gene amplification with fluorescence in situ hybridization (FISH) and screened for EGFR mutations in exons 18-21 using PCR and direct sequencing. All 13 tumors showed strong diffuse or focal EGFR expression. No amplifications of the EGFR gene were found. In contrast, several point mutations were identified in exons 18-21 of two synovial sarcomas. Whereas one of these tumors carried only a synonymous mutation, two missense mutations in exons 19 and 21 of the EGFR gene (P733S and A840 T, respectively) could be demonstrated in the second sample. In conclusion, strong EGFR expression in synovial sarcomas is not related to gene amplification. The existence of mutations in the tyrosine kinase domain of the EGFR gene in a small subset of synovial sarcomas suggests that only few patients may profit from the tyrosine kinase inhibitor therapy.