Psoriasis is a T-cell mediated chronic systemic inflammatory skin disease. Emerging evidences suggest the interleukin (IL)-12B and IL-23R genes encoding the common p40 subunit of IL-12 and IL-23 are the key cytokines in T-helper (Th)1 and Th17 differentiation and function. Certain allelic variants of these genes significantly influence the risk of psoriasis. Hence we undertook to study the association of IL-12B and IL-23R gene polymorphisms with disease susceptibility in South Indian Tamil patients with psoriasis.360 psoriatics and 360 healthy controls were included in this case control study. IL-12B gene (rs3212227) and IL-23R gene (rs2201841, rs10889677 and rs11805303) polymorphisms were typed by using TaqMan 5'allele discrimination assay and cytokine levels were assayed by ELISA.We observed that the patients carrying the risk genotypes of IL-12B (rs3212227) and IL-23R (rs2201841) conferred an increased susceptibility to psoriasis. We did not find any significant association between IL-23R (rs10889677 and rs11805303) gene polymorphisms and psoriasis risk in South Indian Tamil population. We did not observe any significant difference in haplotypes between the psoriasis cases and controls. We observed a significant increase in the mean IL-23 levels in psoriatics and the higher levels of IL-23 were found in the minor variant genotype CC when compared with that of heterozygous CT and major variant TT genotypes of rs2201841. Individual genotypes of rs10889677 and rs11805303 and IL-12 (rs3212227) were not significantly associated with their plasma levels.Our results suggest that IL-12B (rs3212227) and IL-23R (rs2201841) polymorphisms confer increased risk of psoriasis in our ethnic South Indian Tamils.