Psoriasis is an inflammatory skin disease of unknown origin, but with a clear genetic component. The strongest genetic association has been found with the major histocompatibility complex (MHC) region, and specifically between susceptibility to familial early onset psoriasis and human leukocyte antigen (HLA)-Cw6. The basis of this association of the HLA-C locus with disease pathogenesis is, however, not clear, and it is possible that other genes, or a combination of genes, in the HLA region are of functional importance. The MHC S gene is expressed specifically in keratinocyte differentiation and, being located 160 kb telomeric of HLA-C, is a plausible candidate gene. We analysed the allelic distribution of two polymorphisms in the MHC S gene (at +619 and +1243) in a case-control association study. We could confirm a significant association between psoriasis and HLA-Cw6 [odds ratio (OR) = 7.75]. No association was found between disease (or any subtypes) and the MHC S gene polymorphism at position +619, despite its close proximity to HLA-C and the strong linkage disequilibrium between the loci. However, a significant trend with the rarer allele at MHC S (+1243) and psoriasis was detected in the overall data set (OR = 2. 66; P = 2 [times] 10(-)9). This effect was most pronounced in the type 1a (early onset) psoriatics (OR = 3.43). Furthermore, homozygosity for the associated allele at MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6 alone (OR = 9. 38), suggesting that allele 2 of MHC S (+1243) provides an additional risk in psoriasis susceptibility. The strong association found here, coupled with the biological involvement of the MHC S gene product corneodesmosin in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S ) in the impaired desquamation characteristic of psoriasis.