SCC antigen (Ag) is a tumor-associated Ag (TAA) obtained from squamous cell carcinoma of the uterine cervix. This study reports the evaluation of this TAA in patients with head and neck malignant diseases and its possible prognostic value. Serum samples from 28 patients with benign head and neck diseases from 399 patients with cancer were obtained prior to treatment. SCC Ag serum levels were determined by radioimmunoassay using 2.5 ng/ml as the upper limit of normality. Elevated SCC Ag serum levels were found in 14% of 28 patients with benign diseases, in 29% of 217 patients with primary tumors, in 48% of 46 patients with recurrence (43% in locoregional, 64% in metastases) and in 4% of 136 patients with no evidence of disease. In patients with primary tumors, SCC Ag serum levels were related to nodal involvement and tumor location with significantly higher levels in node-positive patients (p = 0.001) and in tumors located in the nasopharynx and piriform sinus (p = 0.02). Presurgical SCC Ag serum levels in patients with primary tumors had prognostic value with shorter disease-free survival in those patients with abnormal values of this TAA (p < 0.001), in both, node-negative and node-positive patients (p < 0.01). Multivariate analyses showed that SCC Ag is a significant independent predictor of disease-free survival even when other prognostic factors are considered. In conclusion, pretreatment SCC Ag serum levels are an independent prognostic indicator in patients with head and neck malignancies.