The relationship between CCND1 and/or EMS1 amplification and disease outcome was studied in a prospective series of 104 head and neck squamous cell carcinomas treated by surgical resection. The CCND1 and EMS1 copy number in tumor samples was estimated by differential PCR. The presence or absence of amplification was analyzed in relation to clinicopathological variables, tumor recurrence, and patient survival. CCND1 amplification occurred in 32 cases (31%) and was associated with increased lymph node stage (P = 0.005) and advanced disease stage (P = 0.003). EMS1 amplification was identified in 21 cases (20%) and was related with advanced T stages (P = 0.001), increased lymph node stage (P = 0.02), advanced disease stage (P = 0.041), poor histological differentiation (P = 0.018), recurrent disease (P = 0.0004), and reduced disease-specific survival (P < 0.0001). Coamplification of both genes occurred in 11 cases (11.5%). Multivariate analysis confirmed that in addition to regional lymph node status, EMS1 amplification is an independent predictor of death from the tumor (P = 0.0027). CCND1 amplification was not prognostic. These data indicate that EMS1 amplification, but not CCND1 amplification, predicts early recurrence and reduced survival in squamous cell carcinoma of the head and neck. The prognostic significance previously attributed to CCND1 amplification may be attributable to its frequent coamplification with EMS1.