OBJECTIVE To determine (1) the risk of treatment termination for low dose, weekly methotrexate (MTX) therapy in patients with rheumatoid arthritis (RA), and (2) the prevalence, nature and predictors of adverse effects due to longterm low dose MTX therapy. METHODS A 13-year, retrospective survey of all patients with RA receiving low dose MTX therapy was conducted using life table, logistic regression and case control methods of analyses. Major and minor adverse effects were defined. RESULTS Consecutive patients with RA (144) starting MTX (mean dose 8.2 mg/week) were observed to have a 75% risk of treatment termination at 60 months. Reasons for 81 patients stopping MTX were adverse effects (43), loss/lack of effect (18), other medical and nonmedical reasons (13), and lost to followup (7). Sixty-two patients experienced 83 major adverse events, including gastrointestinal symptoms (29), hepatic enzyme test abnormalities (23), pneumonitis (5) and severe leukopenia (8). Aging was the only predictor of treatment discontinuation associated with a major toxicity. Five patients developed a malignancy during the observation period. CONCLUSIONS In our survey the risk of treatment termination was 75% in patients with RA taking MTX after 60 months. An adverse drug effect is a more common reason for treatment termination (53%), compared to loss/lack of beneficial effect (22%) or other reasons (16%) or lost to followup (9%). Increasing age is associated with an increased risk of treatment termination associated with a major toxicity.