Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA. Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers. Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN ( = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors ( = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs ( = 0.038) and when distinguishing according to adverse events (AEs) occurrence ( = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 CI: 1.341-8.406, = 0.01) and those experiencing AEs (HR = 2.970 CI: 1.186-7.435, = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors ( = 0.0002). Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.