Objectives: To evaluate frequency and to identify factors which may increase the discontinuation of Methotrexate (MTX) among Rheumatoid arthritis (RA) patients in Aseer region, KSA. Methods: A cross-sectional study was conducted in Aseer Central Hospital, Southern region, Saudi Arabia that are currently or previously were using MTX. All the patients were included who fulfilled the 1987 revised American Rheumatism Association criteria for classification of RA. Medical records for 200 RA patients were chosen through convenience method then they reviewed and analyzed. Results: A total of 200 RA patients were participated, 169 (84.5%) were female and 31 (15.5%) were female. Their ages ranged from 12 to 80 years with a mean of 45.07 and standard deviation 14.37 years. About 67 (33.5%) patients told that their disease duration was 10 years and more and 147 (73.5%) patients were using MTX and 53 (26.5%) were not using the medication. Out of 147 patients, 24 (27%) of them did not take MTX regularly due to different reasons. The most common side effects were stomach ache as same as indolence and sloth. There is no statistical association between sex, education level and duration of disease and discontinuation at p=0.05. Conclusion: The study concluded a low rate of drug discontinuation due to adverse effects, MTX seems to be a safe drug for long-term use in RA patients. More attempts should be done to minimize side effects and discontinuation of MTX, in order to get the benefits of drug considered as the cornerstone in RA treatment.