Mutagen sensitivity is a constitutional factor which may be used to identify head‐and‐neck squamous‐cell carcinoma (HNSCC) patients at high risk for the development of multiple primary tumors (MPT). In this retrospective study, mutagen sensitivity was measured in HNSCC patients with a single primary tumor (SPT), HNSCC patients who have already developed MPT and control subjects with no tumor history. In vitro, lymphocytes were challenged with bleomycin and chromosomal damage was quantified by scoring chromatid breaks of 100 cells. A significant difference in the mean number of breaks per cell (b/c) was found between SPT patients and controls. Patients with MPT showed a significantly higher mean b/c value than SPT patients. This increase in mutagen sensitivity in HNSCC patients was not related to well‐known cancer risk factors such as age, or life‐style factors such as smoking and alcohol drinking habits. In addition, tumor site but not tumor stage was found to be related to mutagen sensitivity. On the basis of our findings, we propose that mutagen sensitivity is not an independent risk factor but a constitutional factor which reflects the way in which genotoxic compounds are dealt with and is thereby directly related to cancer risk.