Numerous putative susceptibility loci have been described for psoriasis. Among the loci confirmed in the literature, PSORS1 (the major histocompatibility complex at 6p21.3) has the strongest effect. Recent studies have highlighted a 200-kb candidate region. However, this region has not been well delimited, mainly because of the strong linkage equilibrium among the associated alleles. To finely map PSORS1, we set up a study using 17 polymorphic markers in a 525-kb interval around the human leucocyte antigen C locus (HLA-C). The results uncovered five loci with alleles strongly associated with psoriasis (Sidak-corrected P [P(c)] values from 1.8 x 10(-7) to .003), all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present on the traditional psoriasis-susceptibility extended haplotypes (HLA-Cw6-B57, HLA-Cw6-B37, and HLA-Cw6-B13) but also on a haplotype of Sardinian origin (HLA-Cw7-B58) found to be associated with psoriasis (Pc=.0009) because of an ancestral recombination with one of the susceptibility haplotypes carrying the HLA-Cw6 allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, around the corneodesmosin (CDSN) gene.