The objective of the present study was to assess the rate of side-effects and dose-limiting toxicity in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX) at an initial dose of 15 or 25 mg/week. One hundred and eighty-five patients with active RA were enrolled into a prospective non-blind trial over 12 months and randomized to start at a dose of 15 mg/week with subsequent increases if necessary (group A) or 25 mg/week with subsequent dose reductions according to effect (group B). With 168 patients eligible for evaluation 74% of patient in group A and 73% of patients in group B were on MTX after 12 months. Withdrawal due to side-effects amounted to 16% of patients in group A and 18% in group B, and decreases in dose due to side-effects amounted to 10% in group A and 9% in group B. The higher dose of MTX elicited a significantly higher rate of gastrointestinal side-effects (28% versus 17%, P < 0.05) and a tendency towards a higher rate of liver enzyme elevations (47% versus 39%). The frequencies of other side-effects did not differ significantly between the groups. We concluded that starting MTX treatment at a dose of 25 mg/week was associated with a higher rate of minor but not major toxicity as compared with 15 mg/week. With this profile of tolerability it is possible to examine the therapeutic potential of MTX doses exceeding 15 mg/week.