<i>Background/Aims:</i> RCAS-1 is a transmembrane protein that is involved in the evasion of host immune surveillance by tumor cells. It has been found to be a valuable prognostic and diagnostic marker in a number of different malignancies. The objective of the study was to analyze the potency of RCAS-1 as a biomarker in the serum of patients with head and neck squamous cell carcinoma (HNSCC). <i>Methods:</i> ELISA was performed with prospectively collected serum samples from 60 patients with HNSCC (taken at the time of diagnosis, after 3 and 12 months) and from 31 healthy controls. To correlate serum levels with RCAS-1 expression in the tumor, immunohistochemical staining of RCAS-1 was done using a tissue microarray. <i>Results:</i> Surprisingly, median sRCAS-1 levels were basically identical between tumor patients and controls. Interestingly, patients with low RCAS-1 values at the time of diagnosis had better disease-free survival. 62% of tumor samples expressed RCAS-1 but we could not demonstrate a correlation between protein expression and serum levels. <i>Conclusion:</i> This study was the first to correlate RCAS-1 levels in the serum and in the tumor of the same patients. RCAS-1 seems to have prognostic properties although larger studies will be necessary to fully evaluate its role in HNSCC.