Adherence studies among rheumatoid arthritis (RA) patients, in Egypt and throughout the Middle East region, are lacking. This study aimed to evaluate methotrexate (MTX) adherence in Rheumatoid arthritis (RA) patients and to identify specific non-adherence predictors. A cross-sectional observational study included 300 RA patients who were administered MTX for at least one year. The survey was completed through direct interviews. The demographic patient data were collected (age, education, sex, work status, disease duration, duration of MTX administration and current dose). Patients' adherence to MTX predictors for non-adherence, MTX side effects and functional disability were assessed in the study. Majority of respondents showed good MTX adherence, and more than 50% of patient's experienced MTX side effects. A large percentage of participants showed low knowledge about MTX nature and side effects. Most participants reported no or some difficulty in quality of life-related activities and functional disability. MTX adherence and awareness were positively correlated to many variables, including, age, educational level and disease duration, which in turn has its positive impact on the patient's quality of life. Still, more research is needed to determine the impact of non-adherence on the patient's health outcomes.