Objectives: Psoriasis is an inflammatory skin disease, and the main topical treatment for this disease is corticosteroids, vitamin D analogs, salicylic acid, and calcineurin inhibitors. This study clinically evaluates a topical dosage form of methotrexate (MTX) micro-emulsion and compares it with clobetasol lotion. Methods: The employed methodology involves 20 patients with symmetric psoriasis. Topical MTX micro-emulsion (0.25%) was used on one side and clobetasol lotion (0.05%) on the other side. The psoriasis area and severity index score were used to evaluate the results in weeks 0, 4 and 8. Results: The average psoriasis improvement and psoriasis area and severity index score reduction using topical MTX micro-emulsion were 47.24%±10.1524% and 73.5%±6.34% at the end of the first and second months of treatment. The results using clobetasol lotion were 56.5%±8.08% and 73.4%±7.27% after the first and second months of treatment, respectively. There was a significant statistical difference between MTX micro-emulsion and clobetasol lotion after the first month of treatment (α=0.005); however, this difference was not significant after the second month (α=0.938). Discussion: The application of topical MTX micro-emulsion can be effective in improving psoriasis and is much safer compared to injectable forms.