A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04 months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65 years compared with patients < 16 years ( p  = 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants ( p  = 0.055), but a significant difference was observed when injection site reactions were excluded from AE ( p  = 0.01). No differences were identified in relation to gender ( p  = 0.462), different lines of biologic therapy ( p  = 0.775), and different dosages ( p  = 0.70 ANA; p  = 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns ( p value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA ( p  < 0.0001 ANA; p >  0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 C.I. 0.250–0.638, p  = 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.