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Introduction: Oral methotrexate (MTX) is the first-line therapy for patients with rheumatoid arthritis (RA). However, not all RA patients respond to MTX. In this study, we will determine the risk factors associated with MTX failure., Methods: This retrospective study was conducted in tertiary care hospital in Pakistan. Data of 612 patients who were diagnosed with RA from June 2019 to January 2021 were retrieved from the medical record room. After inclusion, patients were divided into two groups; respondent and non-respondent. Their characteristics and demographics were compared., Results: Out of the total 612 patients, 112 (18.3%) were labelled as non-respondent to MTX. Non-respondents had a higher predominance of females (86.6% vs. 60.2%; p-value: 0.001), participants with body mass index (BMI) >25 kg/m 2 (54.4% vs. 22.4%; p-value: <0.00001), smokers (34.8% vs. 18.2%; p-value: 0.0001), participants with diabetes (47.3% vs. 23.4%; p-value: <0.0001) and rheumatoid factor positivity (91.0% vs. 64.8%; p-value: <0.0001)., Conclusion: Female gender, higher BMI, smoking, higher disease activity, and diabetes were associated with MTX failure. These easily available parameters can help predict the disease process and outcome of treatment. It is important to screen patients who are at risk of MTX failure, so a contingent treatment plan can be devised, in case patients do not respond to MTX., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Siddiqui et al.)