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Background: Psoriasis is an inflammatory systemic disease with a chronic relapsing course. Methotrexate, a dihydrofolate reductase inhibitor, and Apremilast, an oral phosphodiesterase type 4 inhibitor, are currently the mainstay drugs in the treatment of psoriasis. Aims and Objectives: To compare the efficacy of Methotrexate with a combination of Methotrexate and Apremilast in treating chronic plaque psoriasis. Materials and Methods: The present study was a prospective comparative study conducted among 40 patients, aged above 18 years, with clinically diagnosed psoriasis attending Dermatology OPD of a tertiary care hospital in North India. The study utilised a pre-structured proforma to record a detailed demographic profile and clinical examination related to chronic plaque psoriasis. The patients were divided into two groups of 20 each. Group A was treated with oral Methotrexate, while Group B was treated with oral Apremilast and Methotrexate, and they were evaluated every 4 weeks for 12 weeks. Necessary investigations were done wherever indicated. Results: The male-to-female ratio was 1.35, and the majority (55.0%) of patients belonged to the age group of 31-50 years. 27.5% of patients had comorbidities like diabetes, hypertension, etc., The mean PASI score of group A at the first, second and third follow-ups was higher than that of group B. The reduction in mean PASI score was statistically significant in group B at successive follow-ups, with a percentage improvement of 89.4% at the end of 12 weeks. Conclusions: When comparing monotherapy with methotrexate and multidrug therapy with Methotrexate and Apremilast, multidrug therapy had better efficacy. [ABSTRACT FROM AUTHOR]