Objective To evaluate the efficacy and safety of glucocorticoids (GC) monotherapy and GC combined with tacrolimus (TAC) therapy in patients with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD). Methods Through retrospective analysis and propensity score matching (PSM) analysis, the 2-year progression-free survival (PFS) and related side effects of ASS-ILD patients in TAC+GC group and GC monotherapy group were compared. Predictors associated with PFS were analyzed with COX. Results The 2-year PFS rate of TAC+GC group was better than that of GC group [P=0.0163; hazard ratio (HR) 0.347]; Univariate and multivariate analysis of the COX regression model for 2-year PFS in the two groups suggested that creatine kinase level (P=0.0019, HR 1.002) and initial treatment selection [(TAC+GC) vs. GC, P=0.0197, HR 0.207] were independent predictors of PFS; PSM analysis showed that the 2-year PFS rate of TAC+GC group (54.5%) was higher than that of GC group (18.2%) (P=0.0157, HR 0.275). In terms of adverse effect, there was no significant increase in GC+TAC group compared with GC group. Conclusion Compared with GC monotherapy, initial TAC+GC treatment significantly prolonged PFS in ASS-ILD patients and did not increase the incidence of drug-related complications.