Interleukin-1 plays a key role in inflammation and keratinocyte activation. It is an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target. The aim of this study is to evaluate the effect of Methotrexate (MTX) on IL-1 α and IL-1 β levels in both plasma and skin biopsy of patients with psoriasis and to investigate their association with clinical disease activity. Forty-five control subjects and 58 patients with psoriasis were recruited for this study. The patients were treated with 7.5 mg of MTX per week for 12 weeks. Folic acid was given at 5 mg once daily except on the day of MTX for 12 weeks. Blood samples and lesional skin biopsy were taken. Disease severity was assessed by Psoriasis Area Severity Index (PASI) score. IL-1 levels in plasma and skin biopsy were analysed using ELISA. PASI score declined significantly (P < 0.001) from day 0 to 12 weeks of MTX treatment. IL-1 α level in plasma and skin biopsy was reduced at day 0 sample and elevated significantly (P < 0.001) after MTX treatment. IL-1β level in plasma and skin biopsy was higher at day 0 sample and reduced significantly (P < 0.001) after MTX treatment. IL-1α levels and PASI score showed inverse correlation score before and after treatment with MTX. Whereas IL-1β levels showed positive correlation before and after treatment with MTX. Decreasing IL-1β levels by MTXs in psoriasis may block the Th17 differentiation. This shows the therapeutic effect of MTX in controlling the immunopathogenesis of psoriasis.