To compare the relative safety and efficacy of azathioprine (AZA), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA).

Two hundred twelve patients with active RA were entered into a 24-week prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups.

One hundred fifty-eight patients finished 24 weeks of the study. There were no remissions seen but response rates were greater than 30% for all outcome measures. Combination therapy was not statistically superior to MTX therapy alone, but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures. If only patients who continued taking the therapy were analyzed, the mean improvement was greater for AZA therapy than for MTX, while the combination remained the most active. Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations.

Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment.