OBJECTIVES: Safety is a concern for solid-organ transplant (SOT) recipients with systemic inflammatory diseases (SID) treated with biologic therapy. This study evaluated the safety of biologic therapy in SOT recipients with SID. METHODS: This retrospective study between 2000-2024 included 20 biologic-treated SOT recipients with SID matched to 56 SOT recipients controls without SID not treated with biologic therapy. The study compared post-transplant safety outcomes, with serious infections defined as the primary outcome. Kaplan-Meier survival analysis evaluated time-to-safety event outcomes. RESULTS: The biologic-treated group included patients with mainly inflammatory bowel disease and Familial Mediterranean Fever treated with TNF and IL-1 inhibitors, respectively, with 60% (n = 12) treated with biologics over 5 years post-SOT. There was a non-significant trend for serious infections in the biologic-treated group vs controls, 40% (n = 8) vs 23.21% (n = 13), p= 0.15, with urinary tract infection being the most prevalent in both groups. Recurrent serious infections were more prevalent in the biologic-treated group vs controls, 20% (n = 4) vs 12.5% (n = 2), p= 0.029. No opportunistic infections were observed. No graft rejection occurred in the biologic-treated group compared with 5.37% in controls. Cancer rates were comparable in the biologic-treated group vs controls, 15% vs 7.14%, p= 0.3. There were 2 deaths attributed to COVID-19 infection and a car accident compared with none in the control group, p= 0.003. There were 6 cases of biologic treatment discontinuation, mainly due to loss of efficacy. CONCLUSION: This real-world cohort based on 5-year follow-up since the post-SOT biologic initiation supports the feasibility of biologic therapy in SOT recipients with SID.