CYFRA 21-1 was compared to the most reliable tumor markers for squamous cell carcinoma of the head and neck (HNSCC), SCC antigen and CEA. Sera of 163 patients with primary and 40 patients with recurrent HNSCC were examined. 94 patients with non-malignant ENT-diseases served as the control group. To give a specificity of 95% the cut-off-values were as follows: SCC: 1.9 ng/ml, CEA: 3.8 ng/ml, CYFRA 21-1: 2.9 ng/ml. SCC had the highest sensitivity at the time of primary diagnosis (P) at 43% and 61% at relapse (R), compared to CEA with P: 35%, R: 40% and CYFRA 21-1 with P: 17%, R: 18%. We show that CYFRA 21-1 cannot offer additional information to the clinical outcome of patients with HNSCC, whereas combined analysis of SCC and CEA leads to a markedly increased sensitivity of 60% at primary diagnosis and of 79% in cases of tumor relapse.