Background: Psoriasis is a chronic, relapsing, inflammatory, and hyperproliferative skin disease. The growth of keratinocytes is regulated by a delicate balance between molecules controlling cell survival (such as Bcl2) and cell death (such as p53). The study was conducted to observe the clinical and histopathological effect of Methotrexate on psoriatic lesions. Materials & Methods: The immunohistochemical expression of pro-apoptotic (p53) and anti-apoptotic (Bcl2) proteins was correlated with histomorphological changes (epidermal thickness, munro microabscess, granular layer, lymphocytic infiltrate, blood vessels) in the psoriatic skin. Results: A total of 35 cases of psoriasis were studied. Male predominance was seen and trunk was the initial site of involvement in 40% cases. There was a significant reduction in PASI (Psoriasis Area Severity Index) score, grade 3 cases of psoriasis and mean expression of p53 in all the histomorphological parameters in the subsequent 2 and 6 weeks of methotrexate therapy. The expression of p53 in all parameters and Bcl2 in the lymphocytes is significantly higher (p <0.05) in psoriatic skin as compared to the normal skin (control group). Conclusion: Low dose of methotrexate (0.3-0.5 mg/kg) contribute to reduction in epidermal thickness and thereby remain an effective therapy for psoriasis.