AbstractThe risk of developing skin cancers is dependent on a combination of environmental factors and personal genetic predispositions. Basal cell carcinoma (BCC) has been associated with single nucleotide polymorphisms in several pigmentation genes; however, there is still controversy concerning the mechanism by which these variants may increase the risk of BCC. The pathway may lead to pigmentation alone, but evidence for their independent influence is growing. Using a single base extension protocol, candidate polymorphisms within 11 known pigment‐related genes were studied for their association with BCC in a population sample consisting of 164 patients and 707 controls. The significance of variation within the MC1R gene was confirmed and, in addition, position rs12203592 within the IRF4 gene was shown to be associated with BCC. These associations remained significant after adjustment for skin color. Gene–gene interactions were found to influence susceptibility to BCC. Among interacting genes are the two above‐mentioned loci with main effect on BCC risk and additionally KITLG, TYRP1, ASIP and TYR. The obtained results indicate that polymorphism at MC1R and IRF4 constitute pigmentation‐independent risk factor in the development of BCC. Moreover, susceptibility to BCC may be influenced by epistatic effects between pigmentation genes.