Psoriasis is an inflammatory skin disorder that exhibits multifactorial mode of inheritance. In addition to the well-known susceptibility locus PSORS1 many other loci have been shown to be implicated in the genetic predisposition for disease. However, interactions between loci have not been thoroughly explored. Thus, we measured the effect of potential interaction between human leukocyte antigen (HLA)-C, CSTA and D1S236 at PSORS1, PSORS4 and PSORS5, respectively, in the development of psoriasis. Analysis of 130 Caucasian psoriatic families showed that the risk to an HLA-Cw6 +ve individual who carries two copies of the risk allele at both the CSTA and D1S2346 is 105 times the risk to an HLA-Cw6 +ve individual who does not carry any risk alleles at the CSTA or D1S2346. This is the first demonstration of an interaction between risk alleles in three susceptibility loci suggesting possible functional interaction between genes in these loci, which might explain the complexity of the pathogenesis of psoriasis.