Previous studies have indicated that oxidative stress contributes in the efficacy and toxicity of methotrexate (MTX) treatment. The present study aims to investigate the systemic MTX treatments impact on the total oxidant and antioxidant status of the patients with psoriasis. A total of 26 psoriasis patients were included in the study. Serum total oxidant status (TOS), total antioxidant status (TAS), and serum paraoxonase enzyme (PON) levels were measurement of all patients, and Oxidative Stress Index (OSI) were calculated before and after 8 weeks of MTX therapy. Psoriasis Area Severity Index scores of the patients decreased significantly after MTX treatment. While the serum concentrations of total cholesterol, low density lipoprotein, and high density lipoprotein decreased significantly, the serum ALT levels of the patients increased significantly after MTX treatment. There was no statistically significant alteration in serum levels of PON, TAS, TOS, and OSI after the MTX therapy. The oxidative stress emerging with 8-week MTX treatment is not significantly increased in the patients. In parallel with the decreasing inflammation by MTX treatment in patients with psoriasis, a decrease in oxidative stress (OS) is also expected. However, the expected reduction in OS might have been precluded by MTX-induced OS, which resulted in no significant difference between pre- and post-treatment values of OS parameters in our study. There is a possibility that the 8-week results may change with longer treatment durations and higher cumulative doses.