OBJECTIVES: Immunosuppression by biologic response modifiers is essential for successful organ transplantation. These medications have safety concerns that complicate organ transplantation. This study aims to identify and characterize safety signals of serious adverse events associated with exposure to BRM among organ transplant patients. METHODS: Empirica Signal (version 7.3) was used to apply pharmacovigilance disproportionality analysis to the FDA Adverse Event Reporting System to identify serious adverse events. Associations between drugs and events were measured by Empirical Bayes Geometric mean (EBGM) and corresponding 95% confidence intervals (EB05-EB95). Associations with EB05 >1 are considered identified safety signals, and associations with EBGM ≥2 are considered significant safety signals that warrants regulatory follow up and possible actions. RESULTS: From Q4 1997 to Q2 2012, a total of 12,151 serious adverse event reports for biologic response modifiers were reported and 15.6% of them met safety signal threshold. About 12% of these signals were significant. Sirolimus and Mycophenolate accounted for the majority of all signals, and Antithymocyte Immunoglobulin and Cyclosporine contributed to the majority of significant signals. The following significant signals were identified for Antithymocyte Immunoglobulin (reduced therapeutic response, pulmonary edema, hypotention, serum sickness, infusion related reaction, and anaphylactic reaction); for Azathioprine (alternaria infection, fungal skin infection, and lymphoproliferative disorder); for Cyclosporine (neurotoxicity, graft versus host disease, and thyroid cancer); for Cyclophosphamide (disease progression); for Daclizumab (cytomegalovirus infection); and for Tacrolimus (coma and tremor). Approximately 34% of these events contributed to patient death; 7% were life-theratening; 32% lead to initial or prolonged hospitalization; and 28% contributed to other serious outcomes. CONCLUSIONS: Exposure to biologic response modifiers for the prophylaxis against transplant rejection is associated with serious adverse events that could be fatal or life-threatening. Pharmacoepidemiological studies are required to evaluate the identified signals to help understand the benefit-risk profile of these medications.