OBJECTIVE The aim of this study is to document adverse drug reactions (ARDs) of methotrexate (MTX) in Saudi patients. METHODS Cross sectional study of adult patients on MTX, attending rheumatology drug monitoring clinics in a university hospital, over a period of 24 weeks. Adverse drug reactions were sought by patient interview, files review and laboratory abnormalities. RESULTS Data collected included patients' demographics, diagnoses, co-morbidities, MTX dose and duration, other medications, laboratory abnormalities and adverse reactions, their severity, preventability, and outcome. Out of a total of 593 patients screened, 186 (31.4%) using MTX were interviewed. Most of the patients were female (88.5%). Adverse drug reactions (ADRs) were detected in 61 patients (32.8%). Patients with ADRs took a mean dose of 12.9 mg (2.5-22.5 mg). Ten ADRs (16.4% of total reactions) were preventable; they ranged between severe, moderate and mild. The most common ADRs were gastrointestinal (GI) (52.5%), followed by anemia (8.2%) and chest tightness (6.6%). The duration of the reaction ranged from few hours to 4 years. CONCLUSIONS In conclusion our patients with adverse reactions were younger, took less medications and had less co-morbidities. Our results were different from those published in the literature relating MTX toxicity.