Objective. To investigate the clinical efficacy, safety, tolerability, and toxicity profile of a metabolically stable antifolate, CH-1504, compared to methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). Methods. A 24-week open-label trial of MTX and CH-1504 was performed in 20 patients with RA. Results. Improvements in clinical and laboratory indicators were observed in both study groups. Improvement in the CH-1504 group was greater than in the MTX group. Both treatments were generally well tolerated; however, the liver function test abnormalities and gastrointestinal related adverse events expected with this class of medication were not seen with CH-1504. Conclusion. CH-1504 appears to be clinically efficacious and may possess a superior safety and tolerance profile compared to MTX.