This study investigates the role of two nonsynonymous single nucleotide polymorphisms in DNA repair genes, X-ray repair cross-complementing group 1 (XRCC1)-R399Q and X-ray repair cross-complementing group 3 (XRCC3)-T241M, in breast cancer. Incident cases of invasive breast cancer in Caucasian women [n = 402, mean age = 45.7 (SD = 6.2) years] and female Caucasian controls [n = 402, mean age = 45.2 (6.5) years] frequency matched on 5-year age intervals were identified from the Ontario Familial Breast Cancer Registry. No evidence for a main effect of the XRCC1-R399Q genotype on breast cancer risk was observed. Estimates of risk for a family history (FH) of breast cancer compared with no FH differed by XRCC1-R399Q genotype (P value for interaction = 0.001). Homozygote XRCC1-399 R/R individuals and FH+ were at a 2.92-fold [95% confidence interval (95% CI) = 1.47-5.79] increased risk of disease compared with FH- individuals; the estimate of risk increased for R/Q heterozygotes with FH+ [odds ratio (OR) = 3.85, 95% CI = 1.94-7.65] but not for Q/Q homozygotes with FH+ (OR = 0.54, 95% CI = 0.20-1.47) compared with homozygous R/R and FH- individuals. A marginal positive association for XRCC3-241 M/M compared with T/T genotype was found (OR = 1.44, 95% CI = 0.94-2.19), but the heterozygous T/M was not associated with an increase in risk (OR = 0.96, 95% CI = 0.71-1.32). There was also some evidence for a combined effect of body mass index and XRCC3-T241M on estimates of risk. Our results suggest that these polymorphisms may influence breast cancer risk by modifying the effect of risk factors such as FH. There is a need for further study into the role of these polymorphisms as effect modifiers.