We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3′-untranslated-region SNP ( rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio OR common 0.64, combined P P comb=7.85×10 −10). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele ( rs6887695) located ∼60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR common 1.40, P comb=8.11×10 −9) and a less frequent protective haplotype (OR common 0.58, P comb=5.65×10 −12), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines ( IL12A and IL23A) and their receptors ( IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR common 1.44, P comb=3.13×10 −6). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR common 1.66, P comb=1.33×10 −8). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.