INTRODUCTION: Thrombotic microangiopathy (TMA), characterized by small-vessel thrombosis caused by endothelial injury, presents significant diagnostic and treatment challenges in kidney transplantation. METHODS: To investigate the factors associated with posttransplant TMA, we conducted a retrospective study of 3535 kidney transplant recipients at our center from 2008 to 2023. RESULTS: Sixty-eight patients were diagnosed with TMA, and 93% (63 of 68) underwent genetic testing. Patients were categorized into 3 groups based on the TMA etiology. Group 1 ( = 42, 62%) included patients with complement-mediated TMA associated with genetic or acquired complement abnormalities. These patients were younger and had a higher incidence of hypertension (HTN) or preeclampsia as the causes of end-stage kidney disease (ESKD). Notably, 33% of patients developed recurrent TMA, and approximately 78% of those with recurrent TMA lost their allografts. Group 2 ( = 14, 21%) had TMA associated with calcineurin inhibitors (CNIs) or ischemia-reperfusion injury (IRI), showing longer cold ischemia times (CITs) (19.9 ± 8.7 hours vs. 10.7 ± 8.9 hours;  = 0.0001) and a higher rate of delayed graft function (DGF) (43% vs. 13%,  = 0.0008) than the controls. Group 3 ( = 12, 17%) had TMA from diverse causes (infections or autoimmune disorders) and exhibited a poor response to anticomplement therapy. No genetic variants were identified in this group. CONCLUSION: Our findings underscore the need for comprehensive pre and posttransplantation genetic testing to predict and manage the risk of TMA and prevent graft loss. CNIs may exacerbate the risk of posttransplant TMA in the presence of other complement-activating factors. Our study also highlights the importance of personalized strategies and early interventions based on the functional assessment of variants of uncertain significance (VUS).