OBJECTIVES: To study the efficacy in terms of muscle strength, and corticosteroid tapering as well as the prevalence of adverse effects in patients with the antisynthetase syndrome (ASyS) treated with azathioprine (AZA) compared to those treated with methotrexate (MTX). METHODS: We compared the clinical outcomes in ASyS patients treated with AZA versus MTX including change in corticosteroid dose, strength, and creatine kinase (CK) as well as the prevalence of adverse effects. RESULTS: Among 169 patients with ASyS, 102 were treated at some point exclusively with either AZA or MTX (± corticosteroids). There were no significant differences in the rate of muscle strength recovery, CK decrease or corticosteroid tapering between those ASyS patients treated with MTX versus AZA. The prevalence of adverse events in patients treated with AZA and MTX was similar (29% vs. 25%, p>0.05); elevated liver enzymes (17% AZA vs. 12% MTX) and gastrointestinal involvement (10% AZA vs. 8% MTX) were the most common adverse events. While no patients treated with AZA developed lung complications, two of the patients treated with MTX experienced reversible pneumonitis with MTX cessation. CONCLUSIONS: AZA and MTX showed similar efficacy and adverse events in patients with ASyS. Pneumonitis is a rare but important event in patients receiving MTX.