OBJECTIVES: Psoriasis is a chronic inflammatory disease showing co-existence with metabolic syndrome (MS), as has been confirmed by numerous epidemiologic studies in recent times. In this study, the aim was to ascertain the beneficial effects of pioglitazone in psoriasis, simultaneously targeting the improvement of MS parameters. MATERIALS AND METHODS: We conducted a prospective randomized open-labeled parallel-group interventional study in patients of moderate-to-severe chronic plaque psoriasis. A total of 90 patients were inducted in study and divided into three groups of standard treatment (methotrexate 7.5 mg/week for 12 weeks), active treatment (pioglitazone 15 mg tablets once daily for 12 weeks), and their combination. Primary outcome was taken as percentage Psoriasis Area and Severity Index (PASI) improvement from baseline; secondary outcomes were PASI-75, safety profile, and MS parameters. RESULTS: Intergroup evaluation of PASI score showed that standard treatment methotrexate and active treatment pioglitazone were comparable. Combination of methotrexate and pioglitazone proved superior in efficacy from both standard and active treatment in 8 and 12 weeks. Adverse drug reactions were mild and treated symptomatically. Pioglitazone and combination group also demonstrated beneficial efficacy in parameter of MS hence establishing it as a potential therapy in psoriasis with MS. CONCLUSIONS: Pioglitazone alone or in combination with standard treatment may be a safe alternative drug for psoriasis coexisting with MS proving beneficial for both.