Correlations among epidermal growth factor receptor (EGFR) gene amplification, mutation, and overexpression/activation of proteins were investigated in 39 cases of bone/soft tissue tumors (BSTTs). By immunohistochemistry, EGFR overexpression was found in 22.6% of sarcomas, but not in benign lesions. By immunoblotting, among sarcoma cases showing upregulation of EGFR, 47.4% showed EGFR activation. In 2 cases of malignant fibrous histiocytoma with high level of EGFR gene copy numbers, EGFR expression and phosphorylation levels were significantly higher; and signal transducer and activator of transcription 3 (Stat-3) was activated. Point mutations were detected in 4 cases, 3 of which were missense mutations. In these 3 cases, activation of EGFR and Stat-3 was found in 2 cases. In the cases without gene aberrations, upregulation of the EGFR was found in both sarcomas and benign lesions; but activation was found only in sarcomas. However, EGFR activation did not specifically correlate with activation of particular downstream molecules. Among the 3 downstream cascades, Akt pathway was more frequently activated than those of Stat-3 or extracellular signal-related protein kinase 1/2, and Stat-3 was activated in tumors exhibiting an epithelial nature, including synovial sarcoma and chordoma. These results suggest that persistent Stat-3 activation may be a critical event downstream of overexpressed EGFR by high level of EGFR gene copy numbers. In contrast, tumors harboring EGFR mutation may not necessarily activate EGFR or specific downstream cascades. Finally, in BSTTs, Akt functions as a predominant molecule. These overall results could provide novel insights into the involvement of EGFR and downstream molecules and suggest that EGFR-mediated cascades are candidates for molecular targeting therapy in defined subsets of BSTTs.