Head and neck cancers (HNCs) are malignancies that can be induced by tobacco use, although host-specific factors such as the DNA repair capacity (DRC) may modulate individual susceptibility to tobacco carcinogenesis. To test the hypothesis that genetically determined DRC modulates HNC susceptibility, we measured the DRC in the peripheral blood lymphocytes of 55 patients with newly diagnosed, previously untreated HNC and 61 healthy controls by the host-cell reactivation assay using a reporter gene damaged by benzo(a)pyrene diol epoxide, an ultimate tobacco-related carcinogen. The mean DRC was significantly lower in cases (8.6%) than it was in controls (12.4%; P < 0.001). The DRC was an independent risk factor for HNC (P < 0.01); those in the middle and lowest tertiles of DRC had increased odds ratios [2.17 (95% confidence interval, 0.74-6.39) and 4.27 (confidence interval, 1.45-12.5), respectively] for HNC. These findings suggest that individuals with reduced DRC may be at increased risk of developing HNC.