The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). Although environmental exposures, especially solar UV-irradiation, have been implicated as risk factors in sporadic melanoma, the role of such exposures in the pathogenesis of HCMM is unknown. We have studied the in vitro radiation responses of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. All six HCMM/DNS strains were found to show some degree of enhanced cell killing sensitivity, compared with normal controls, following 254 nm UV-irradiation. The abnormal survival responses appeared to relate to specific characteristics of HCMM/DNS cells since the six strains had essentially normal sensitivity to gamma-radiation. The enhanced photosensitivity was not associated with abnormal patterns in either DNA repair synthesis or UV-induced inhibition and recovery of de novo DNA synthesis. The survival results are consistent with the hypothesis that the genetically determined predisposition to malignant melanoma may directly or indirectly be the consequence of increased susceptibility to UV-induced cellular damage.