Background: During the ongoing COVID-19 pandemic, immunocompromised patients are at a higher risk of severe infection, since the immune system has an important role in defeating this disease. This study compares the severity of COVID-19 in patients taking methotrexate with the severity of their family members' illness as patients with normal immune system function. Methods: A total of 35 participants, including 14 patients taking methotrexate and 21 patients with normal immune function, entered this study, and the indicators of COVID-19 severity were compared between these two groups. Results: The case group, who were on methotrexate therapy, had significantly less severe COVID-19 based on their symptoms, including fever (p = 0.000) and cough and dyspnea (p = 0.01) as well as in terms of COVID-19 severity indicators such as pulmonary involvement (p = 0.001), ferritin level (p = 0.001), white blood cell count (p = 0.008) and CRP level (p = 0.006), compared to the control group. There was a significant correlation between taking methotrexate and lower severity in COVID-19 disease. Conclusion: The present findings demonstrated that methotrexate does not predispose patients to severe COVID19; on the contrary, patients taking methotrexate may experience a milder disease, possibly due to their reduced severe inflammatory reactions as a result of inhibited TNF alpha, lowered IL6, and increased T regulatory cells. According to these findings, methotrexate appears to be a suitable treatment option for patients who need immunosuppressive medications during the COVID-19 pandemic
