Background: Psoriasis is a chronic inflammatory skin disease has a strong genetic predisposition. Aim of the work: To study the role of TNFAIP3 rs610604 (C/A) polymorphism in psoriasis, and its effect on Etanercept response. Subjects and methods: One hundred patients with psoriasis, in addition 100 apparently healthy individuals as a control group were included in this study. Restriction Fragment Length Polymorphism-Polymerase Chain Reaction (RFLP-PCR) was performed to evaluate different TNFAIP3 gene polymorphism. TNFAIP3 serum levels were assessed by enzyme-linked immunosorbent assay. Results: Current study showed low serum level of TNFAIP3 protein in psoriatic patients when compared with control group (P<0.01). A considerably higher risk of psoriasis was observed in individuals who had TNFAIP3 rs610604 SNP CC and C allele than people carrying AA genotype and A allele. In relation to the response to treatment, this study observed that the mutant homozygous genotype CC was more frequent in non -responder (71.4%) than responder (1.3%) patients (P<0.01). Conclusion: TNFAIP3 rs610604 (C/A), might be useful for prognosis of psoriatic patients.