Follow-up examinations of patients might detect local tumor recurrences at a curable stage, which is more difficult for distant metastases (DM). Recently, elevated Cyfra 21-1 serum levels (CySL) could be shown not only to correlate with HNSCC-tumor size but also with development of DM. We focussed on the CySL of 476 HNSCC patients as a first step. At first time diagnosis, besides regular staging procedures, these patients were screened for CySL higher than 3.3 ng/ml. Seventeen out of 476 (3.9%) patients showed DM. Seventeen out of 19 patients (89.5%) presented elevated CySL: A further 830 patients with HNSCC were tested for changes in CySL in the course of disease (cut-off value 3.3 ng/ml). Seventy-one out of 830 patients (8.6%) showed elevated CySL. Tumor growth was found in 50 out of 71 patients (70.4%). In 54% of these patients (27 out of 50) DM were detected. Routine screening for CySL can lead to timely detection of DM in HNSCC, despite its fairly low sensitivity.