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Objective: Antinuclear antibody (ANA)-positive immune thrombocytopenia (ITP) patients have an unsatisfactory prognosis due to the more severe conditions of these patients and poor response to first-line glucocorticoids (GCs). The current study intended to compare the efficacy and safety of AZA plus prednisone and prednisone alone as first-line treatment in ANA-positive ITP patients., Methods: Fifteen ANA-positive ITP patients receiving AZA plus prednisone (AZA + GC group) and eighteen ANA-positive ITP patients receiving prednisone alone (GC group) as first-line treatment were retrospectively enrolled., Results: The complete response (CR) rate (60.0% versus 22.2%) ( P  = 0.038) was increased in the AZA + GC group versus the GC group, while the overall response rate (86.7% versus 55.6%) ( P  = 0.070) only showed an increasing trend that did not achieve statistical significance. In addition, multivariate analysis revealed that AZA + GC (versus GC) (odds ratio = 31.331, P  = 0.018) was independently associated with a higher possibility of achieving CR. Additionally, accumulating relapse-free duration was prolonged in the AZA + GC group versus the GC group (median: 7.8 months versus 3.4 months) ( P  = 0.038). Additionally, the multivariate analysis suggested that AZA + GC (versus GC) (hazard ratio = 0.306, P  = 0.007) was independently correlated with longer accumulating relapse-free duration. The incidence of adverse events did not differ between the two groups (all P  > 0.05), and the common adverse events in the AZA + GC group were pneumonia (13.3%), anemia (13.3%), cough (13.3%), nausea (6.7%), and granulocytopenia (6.7%), which were all tolerable and manageable., Conclusion: First-line AZA plus prednisone realizes a better hematological response and relapse-free duration with acceptable adverse events compared to prednisone alone in ANA-positive ITP patients.