Homologous recombination (HR) is one of the main pathways for the repair of DNA double strand breaks (DSBs). To investigate whether inherited variants in genes encoding proteins that repair DSBs by HR modulate acute myeloid leukaemia (AML) risk, we have examined the frequency of two variants in the 5' untranslated region (UTR) of RAD51 (RAD51 135 G>C and the RAD51 172 G>T) in a large case-control study of acute myeloid leukaemia (AML). Inheritance of a RAD51 135 C allele was associated with a reduced risk of estimate for AML (odds ratio (OR) 0.56, 95% confidence intervals (CI), 0.38-0.83), while the RAD51 172 T allele was not associated with AML. The RAD51 135 and 172 variants were in strong linkage disequilibrium, with three out of the four possible haplotypes being observed in the population. The protective effect associated with the RAD51 135 C allele was found to be associated with inheritance of the RAD51 135-172 C-G haplotype (cases 3.9% versus controls 6.5%, OR 0.61, 95% CI 0.42-0.90). These data suggest that variants in the RAD51 HR gene may modulate genetic predisposition to AML.