Overexpression of p53 as well as the occurrence of serum p53 antibodieshave been correlated to shorter survival and relapse-free intervals in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to reconsider the clinical implications of serum p53 antibodies in HNSCC. Two matched study groups (n=78 patients with HNSCC each), one group positive and one negative for serum p53 antibodies, were followed-up (median of 3 years) regarding the occurrence of relapses, second primaries and tumor related deaths. Tumor relapses (n= 27 vs. 12), second primaries (n= 76 vs. 4) and tumor related deaths (n=21 vs. 9) occurred more frequently in the seropositive group. The results of this study indicate that the presence of serum p53 antibodies in patients with HNSCC points out a group of patients, who have a high risk of treatment failure.