Defective DNA repair capability, measured by enumerating mutagen-induced chromosomal lesions, might explain variable host susceptibility to the action of environmental carcinogens. We compared sensitivity to bleomycin-induced chromosome damage in 75 patients (53 men and 22 women) with previously untreated upper aerodigestive tract malignancies with that in 62 healthy control subjects. Data on tobacco and alcohol use were derived from a detailed, self-administered cancer risk factor questionnaire. Forty-five patients and 13 controls were sensitive to bleomycin-induced mutagenesis (average breaks/cell >0.8). Differential susceptibility was detected in patients categorized by primary tumor location. Odds ratios for chromosome sensitivity were significantly elevated for all sites (odds ratio = 10.3 for pharyngeal cancers, 8.0 for laryngeal cancers, and 3.8 for oral cavity cancers). On logistic regression analysis, chromosome sensitivity remained a strong and independent risk factor after adjustment for potential confounding from age, sex, and tobacco and alcohol use (odds ratio = 4.3, 95% confidence limits = 2.0, 10.2). Despite the small study size and design constraints, the strength of the association with chromosome sensitivity even after adjustment for potential confounders is impressive and suggests a promising avenue for further research. The preventive implications of a valid marker for carcinogen sensitivity are manifold.