Objective.To analyze the characteristics, outcomes, and predictive factors of disease-modifying antirheumatic drug (DMARD) use in 48 patients with antisynthetase syndrome [characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud’s phenomenon (RP), and/or mechanic’s hands] and the presence of anti-histidyl-transfer RNA synthetase (anti-Jo1) autoantibodies.Methods.Forty-eight patients (33 women, 15 men) who were anti-Jo1-positive referred to one center between 1998 and 2008 were analyzed retrospectively.Results.The median age of disease onset was 43 years [interquartile range (IQR) 33–53 yrs]. The median followup was 5 years (IQR 2–8 yrs). At diagnosis, 81% of patients presented with myositis, 80% ILD, 77% arthralgia, 48% RP, and 21% mechanic’s hands. During the followup, 14 patients (29%) had no need for DMARD, while 34 (71%) required DMARD. Patients with mechanic’s hands (p = 0.02) and higher creatine phosphokinase at diagnosis (median 6070 IU/l vs 1121 IU/l; p = 0.002) were more likely to need DMARD. ILD, noted on computed tomography scan by a nonspecific interstitial pneumonia score, was lower in the group of patients with no DMARD need (4 vs 7; p = 0.04). Twenty patients (44%) presented with a pulmonary aggravation (worsening of radiologic score of ILD and/or pulmonary function test results) leading to DMARD use. Nonspecific interstitial pneumonia score (7 vs 5; p = 0.05) and total lung volume (57.5% vs 70%; p = 0.02) values predicted pulmonary aggravation.Conclusion.Our study outlines the burden of chest involvement for the prognosis of antisynthetase syndrome in terms of patients’ requirement for DMARD therapy.