This investigation was designed to test the hypothesis that skin fibroblasts from patients with genetic disorders characterized by hypersusceptibility to X-ray-induced cancer are sensitive to the cytotoxic or clastogenic effects of X-irradiation in vitro. Cell strains were established from 28 specifically ascertained patients from families with nevoid basal cell carcinoma syndrome, retinoblastoma, or other disorders apparently predisposing to radiation-induced cancer. These included 10 patients with a clear personal or family history of radiation-induced tumors. These cell strains were examined for the cytotoxic effects of X-irradiation in 3 distinct series of separate, blinded experiments, along with a group of 9 similarly coded cell bank controls. Cells from 11 of these patients and 6 controls were studied for sensitivity to X-ray-induced chromosomal aberrations. Seven of the 37 cell strains were moderately hypersensitive to radiation-induced cell killing; 2 of these were from patients with radiation-induced tumors and 1 was a cell bank control. These results suggest that such isolated cases of hypersensitivity probably do not relate to the underlying genetic disorder. Overall, the X-ray response of cells from affected individuals in this study showed no systematic difference from that of cells from nonaffected relatives or cell bank controls for either cytotoxicity or clastogenicity.