Despite improvement in therapeutic modalities in head and neck squamous cell carcinoma (HNSCC) the overall survival rate has only marginally improved during the last decades. The occurrence of second primary tumors (SPTs) in the respiratory and upper digestive tract (RUDT) is the main cause of treatment failure in early stage HNSCC. Identification of risk factors for the development of SPT by epidemiological analysis may lead to better risk assessment in individual cases. Ninety-seven HNSCC patients who ultimately developed SPTs and 100 HNSCC patients who remained free of other carcinomas after treatment of the first for a minimal period of 6 years were interviewed about the incidence of RUDT carcinomas within parents and siblings. All questioned patients were smokers. Among the SPT-positive patients, 50 (8.9%) of the 562 family members were reported to have had cancer of the respiratory or upper digestive tract versus 16 (2.5%) of the 629 family members of the SPT-negative patients. This difference was statistically significant (P < 0.0001) with the stratified version of Fisher's exact test. All these 66 probands with RUDT cancer were smokers, and the percentages of smokers were similar in both proband groups. Neither age and sex of the patient, nor tumor stage influenced the occurrence of SPTs in this study. The percentages of probands with tumors outside the RUDTs were almost similar, 8.0 and 7.0% in the SPT-positive and -negative groups, respectively. Having one or more relatives with RUDT cancer was established as a risk factor (odds ratio, 3.8; 95% confidence interval, 2.0-7.6) for patients with initial HNSCC to develop an SPT. These findings suggest that, in addition to external carcinogens, an intrinsic susceptibility may influence the risk for the development of SPTs in HNSCC patients.