The objective of this study was to examine longitudinally the tolerability of methotrexate (MTX) treatment at doses exceeding 15 mg/week in an open-label, prospective study. One hundred and eighty-five patients with rheumatoid arthritis were randomized to receive 15 mg or 25 mg MTX per week initially, and were followed over 30 months. Subsequent dose adjustments according to efficacy and tolerability resulted in levelling off of the mean dose at 18 mg/week, and the original treatment groups were combined for a longitudinal study comparing toxic events during months 1-12 and months 13-30. Withdrawals due to side-effects amounted to 17% during months 1-12 and 4% during months 13-30; dose reductions due to side-effects were 9% and 7%, respectively. The annual incidence of gastrointestinal side-effects increased from 26% to 39% (P = 0.05), that of liver enzyme elevation dropped from 43% to 10% (P < 0.001) and haemocytopenia remained stable at 5% and 7%. MTX pneumonitis was only observed during the first year, while airway complaints without evidence of parenchymal lung involvement increased to 10% beyond the first year. Fifty-six patients experienced 65 major infectious episodes over the 30-month period, with the respiratory tract being the most frequent site. This study showed that MTX treatment at doses exceeding 15 mg/week is tolerated over extended period of time. Major toxicity and withdrawals due to side-effects occurred predominantly during the first year of treatment and thus showed a decreasing trend over time, while minor toxic events continued throughout the study with a progressive rate of mucous membrane toxicity. MTX-treated RA appears to be a risk situation for major infection.