OBJECTIVE Evaluation of Cyfra 21-1 (cytokeratin fraction 21-1) in squamous cell carcinoma of the head and neck. DESIGN Prospective study. PATIENTS Serum Cyfra 21-1 concentration was measured in 250 samples from patients with squamous cell carcinoma of head and neck, patients with benign tumors of head and neck, healthy control subjects, and patients in remission from squamous cell carcinoma of head and neck. RESULTS Cyfra 21-1 concentration was elevated in 60% of the new patients with squamous cell carcinoma but only in 8% of patients with benign tumors and 3.5% of the healthy controls. At a cutoff of 1.3 ng/mL, the sensitivity of the test was 60%, the specificity was 94%, positive predictive value was 75%, and negative predictive value was 89%. The marker levels tended to follow the clinical course of the disease and were useful for therapy monitoring. Cyfra 21-1 levels were in good correlation with the tumor stage expressed by the local (T) and the lymphatic spread (N) and were inversely correlated with histologic grade, eg, higher in poorly differentiated carcinoma than in well-differentiated squamous cell carcinoma. CONCLUSION Cyfra 21-1 evaluation in head and neck squamous cell carcinoma is worthwhile for performance of an ample study that will prove and establish its routine use.