Individuals at increased risk for cancer development have been reported to exhibit increased mutagen sensitivity as detected by the G2 phase chromosome breakage assay. To better understand the basis for such chromosome sensitivity, we examined 4 lymphoblastoid cell lines derived from 4 head and neck cancer patients, 2 of whom were previously shown to have normal bleomycin sensitivity and 2 high bleomycin sensitivity (and multiple primary tumors). These cell lines were studied for cell survival and initial damage and repair at both the DNA and chromosome levels, and the results compared to a normal control cell line and 3 ataxia telangiectasia homozygote cell lines. While all cell lines exhibited nearly equal levels of initial DNA damage and repair throughout the cell cycle, both the ataxia telangiectasia homozygote cell lines and 2 cell lines derived from individuals with multiple head and neck primary tumors showed increased levels of initial chromosome damage (detected by premature chromosome condensation), a reduced fast repair component and higher residual chromosome damage. Our results suggest that one component of the enhanced mutagen sensitivity phenotype observed in cancer-prone individuals may involve an inherent chromatin alteration that allows a more efficient translation of DNA damage into chromosome damage following mutagen exposure. The degree of such an alteration might then be associated with an increased risk for second primary tumors in other carcinogen-exposed sites. © 1995 Wiley-Liss, Inc.