Psoriasis is a chronic inflammatory condition that requires effective treatment. Genetic variability, particularly in the Tumour Necrosis Factor-alpha (TNF-α) gene, may influence patients’ response to biological therapies such as etanercept. This study evaluated the association of four TNF-α gene polymorphisms (rs361525 G/A, rs673 G/A, rs1800629 G/A, and rs1800750 G/A) with serum TNF-α levels and response to etanercept in Iraqi patients with psoriasis. A retrospective study was conducted on 80 patients with moderate-to-severe psoriasis who received etanercept for at least six months. Patients were categorised as responders (≥ 75% PASI reduction) or non-responders (≤ 50% PASI reduction). Genotyping was performed using PCR and Sanger sequencing. A significant association was observed between the rs673 G/A polymorphism and etanercept response: the GA genotype was predominantly present in responders and showed a negative association with non-response (phi = -0.318, p = 0.007), whereas the GG genotype demonstrated a positive association (phi = 0.411, p = 0.0007). Non-responders had significantly higher post-treatment serum TNF-α levels compared with responders. These findings suggest that the rs673 G/A polymorphism and TNF-α levels may be associated with etanercept response. However, larger studies are needed to validate these associations before clinical implementation.