DNA sequence polymorphisms were sought in the coding region and at the exon-intron boundaries of the human XPF gene, which plays a role in nucleotide excision repair. Based on a survey of 38 individuals, we found six single nucleotide polymorphisms, one in the 5' non-coding region of the XPF gene, and five in the 2751 bp coding region. At each site, the frequency of the rarer allele varies from about 0.01 to over 0.38. Except for the 5' non-coding and one coding sequence polymorphism, the rarer alleles for the remaining four polymorphisms were found only in heterozygotes. Of the five polymorphisms in the coding region, one is silent, one results in a conserved amino acid difference, and the remaining three result in non-conserved amino acid differences. Because of its biological function in nucleotide excision repair, functionally significant XPF gene polymorphisms are candidates for influencing cancer susceptibility and overall genetic stability. Nucleotide sequence diversity estimates for XPF are similar to the lipoprotein lipase and beta-globin genes.