Testicular cancer is the most common cancer in young male patients. The combination of cisplatin-based chemotherapy and surgery has resulted in high cure rates. However, a small percentage of patients have cancers that are refractory to chemotherapy; treatment options for these patients are limited, and their prognosis is generally poor. Further studies are needed to explore the molecular pathogenesis pathways and potential targets of therapy for this group of highly aggressive tumors. We analyzed 21 patients who presented with metastatic embryonal carcinoma, were treated with chemotherapy, and subsequently underwent retroperitoneal lymph node dissection. Immunostaining for epidermal growth factor receptor (EGFR) was performed on paraffin-embedded tissue sections containing tumor from these specimens, using the avidin-biotin-peroxidase method. EGFR gene amplification was performed by interphase fluorescence in situ hybridization (FISH). Immunohistochemically, 9 of 21 cases (43%) demonstrated positive EGFR staining; 12 of 21 cases (57%) had absent or very limited EGFR expression. FISH revealed EGFR amplification in 1 case (5%), polysomy in 15 of 21 cases (71%), and normal disomy pattern in 5 of 21 cases (24%). A significant correlation between EGFR protein expression level and its chromosome polysomy/amplification was established (P=0.02). Our study showed that EGFR protein is frequently expressed in a subset of patients with chemorefractory metastatic embryonal carcinoma. EGFR chromosomal polysomy/amplification may be one of the mechanisms that cause increased EGFR protein expression, and could potentially be used as indication for anti-EGFR therapy.