Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a specific complication of allogeneic hematopoietic cell transplantation with a multifactorial etiology. There is little evidence published regarding the efficacy and factors influencing the outcome of substitution of calcineurin inhibitors (CNIs) with other agentsas a widely accepted practice in this disorder; however, there are limited data on the options for immunosuppression manipulation (ISM). In our study, we retrospectively analyzed outcomes of 45 patients with TA‐TMA with ISM and substitution either with steroids (steroid group) or anmTOR inhibitor sirolimus (sirolimus group). In our study, sirolimus was associated with significantly better 1‐year overall survival (HR 0.3, 95% CI 0.13‐0.7, p = .004) and faster time to normalization of LDH (HR 2.2, 95% CI 0.99‐4.99, p = .044). Replacing CNIs with sirolimus could be an effective option in patients with TA‐TMA. A multicenter confirmatory study of CNIs replacement with sirolimus is justified.