Variability in DNA repair capability may be a determinant of interindividual difference in susceptibility to carcinogenic exposures. A cytogenetic assay which quantifies chromosomal breakage induced by in vitro exposure to a clastogen provides an indirect measure of repair. We report the results of a case-control study of upper aerodigestive tract cancers assessing differences in mutagen sensitivity based on this assay. There were 108 cases with previously untreated squamous cell cancers and 108 age and sex frequency-matched controls selected from blood donors to The University of Texas M. D. Anderson Cancer Center. Sixty-nine% of the cases, compared with 44% of the controls, were classified as mutagen sensitive (breaks per cell > or = 0.8). On multivariate analysis, mutagen sensitivity [odds ratio (OR), 2.5], heavy cigarette smoking (OR, 4.8), and heavy alcohol consumption (OR, 3.1) were associated with significantly increased risk. Stratified analyses showed that the combined effects of cigarette smoking (OR, 8.1) and mutagen sensitivity (OR, 3.2) were suggestive of a multiplicative effect (OR, 23.0). The combined estimate for alcohol use (OR, 3.0) and mutagen sensitivity (OR, 3.0) was 5.8. These data confirm those of a previously published preliminary study of upper aerodigestive cancers and underscore the importance of considering interindividual susceptibility in cancer risk characterization, even for those cancers with well quantified exposures.