The purpose of this study was to measure DNA repair capacity and mutagen sensitivity in patients who have had three or more primary forms of cancer. It was hypothesized that, if abnormalities in DNA repair and mutagen sensitivity were cancer susceptibility factors, such findings would be seen with regularity in individuals with multiple primary cancers. DNA repair capacity was measured by determining repair of UV-irradiated plasmid DNA (pCMVCAT) transfected into peripheral blood lymphocytes. Results from 18 patients and a like number of age- and sex-matched controls demonstrated a significant difference in DNA repair capacity (P < 0.0001; odds ratio = 14). Mutagen sensitivity was measured by determining the mean number of chromatid breaks per cell after in vitro exposure to either bleomycin or 4-nitroquinoline-1-oxide. The difference in mean bleomycin- or 4-nitroquinoline-1-oxide-induced mutagen sensitivity between cases and controls was not statistically significant. Fourteen of the 18 patients had positive family histories of cancer; in 10, the history was compatible with cancer susceptibility syndromes. Although the numbers were small, there was no suggestion in this study that treatment or the presence of cancer was the cause of the DNA repair abnormalities encountered. These findings support the concept of diminished DNA repair capacity as an underlying feature in the development of a mutator phenotype.