Inheritance of the T allele in exon 7 (position 18067) of the DNA repair gene XRCC3 has been reported to be associated with susceptibility to melanoma in a study from Oxford. We report a study in which an attempt was made to confirm this association in a similar population. The most potent risk factor for melanoma in the general population is a phenotype characterized by the presence of multiple melanocytic nevi: the atypical mole syndrome. Our hypothesis is that the atypical mole syndrome may be a marker of genetic susceptibility to melanoma. We have therefore investigated whether the XRCC3 polymorphism influences the nevus phenotype. The XRCC3 genotype was investigated using PCR in a general-practice-based sample of 565 women and 475 patients from a cohort enriched for the atypical mole syndrome, of whom 140 had had melanoma. Allele frequencies were the same in the healthy women, the melanoma cases from this study, and the melanoma cases reported in the Oxford study, but were different from those in the Oxford control group. We found no evidence therefore that the T allele of this XRCC3 polymorphism is indicative of susceptibility to melanoma. There was a marginal relationship with nevus phenotype, but this was no longer statistically significant in multivariate analysis. The previous association between XRCC3 and melanoma may be a result of the choice of control group and we emphasize the need for appropriate choice of controls.