The XPD protein has a dual function, both in nucleotide excision repair and in basal transcription. We have studied the role of two nucleotide substitutions in the XPD gene, one in exon 23 leading to an amino acid substitution (Lys751Gln) and one silent in exon 6 in relation to basal cell carcinoma (BCC). Both are two-allele polymorphisms, with the nucleobases A and C at the given positions. We genotyped psoriasis patients with and without BCC and nonpsoriatic persons with and without BCC (4 x 20 persons). The choice to study psoriasis patients was motivated by their high genotoxic exposure via treatment and their high relative rate of early BCC. Subjects carrying two A alleles (AA genotype) in exon 23 were at 4.3-fold higher risk of BCC than subjects with two C alleles (95% CI, 0.79-23.57). In addition, the mean age at first skin tumor for BCC cases with the AA genotype was significantly lower than the mean age for BCC cases with the AC or CC genotype (P = 0.012). Thus, the variant C-allele of exon 23 may be protective. The exon 6 genotype was associated with the risk of BCC among the psoriasis patients; psoriatics carrying two A alleles in exon 6 were at 5.3-fold higher risk of BCC than psoriatics with two C alleles (95% CI, 0.78-36.31). For the psoriatics, the mean age at onset of BCC for cases with the AA genotype was marginally lower than the mean age for cases with genotype AC or CC (P = 0.060). Our results raise the possibility that the polymorphisms in the XPD gene may be contributing factors in the risk of BCC development. They are, therefore, important candidates for future studies in susceptibility to cancer.