Cyclin D1 gene (CCND1) numerical aberrations are independent prognostic indicators of head and neck squamous cell carcinomas (HNSCCs). High epidermal growth factor receptor gene (EGFR) copy number is associated with poor prognosis in lung cancer, but such findings are controversial in oral SCCs (OSCCs). We analyzed copy number status in CCND1 and EGFR in OSCC patients and its association with clinical outcome.EGFR and CCND1 statuses were analyzed in 85 OSCC patients by fluorescence in situ hybridization (FISH) of specimens obtained by fine-needle aspiration biopsy.CCND1 numerical aberration was found in 35 of 85 tumors (41%), and aberrant EGFR copy number was observed in 36 (42%). Gene amplification (GA) was dominant among CCND1 copy number changes (14/35:40%). Balanced trisomy (BT) was the most frequently observed EGFR aberration (17/36:47%). In a multivariate Cox's proportional hazards analysis, CCND1 GA was correlated with disease-free survival (P<0.001), whereas EGFR BT was significantly correlated with overall survival (P=0.001). Patients with a combination of CCND1 GA and/or EGFR BT had significantly poorer clinical outcome.CCND1 and EGFR copy number changes were frequent in OSCC and had differing aberration patterns. CCND1 GA and EGFR BT statuses by dual-color FISH were the predominant predictors of clinical outcome. Further investigation is needed to determine the implications for EGFR inhibitor therapy in OSCC.