This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P=0.005 for bleomycin and P=0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms.