C5-blockers are the established treatment for complement-mediated hemolytic uremic syndrome (CM-HUS). However, CM-HUS, lacking a definitive test, prompts plasma exchanges as a common first-line therapy, pending further assessments, despite complications and limited evidence in this indication. Recent experts’ opinion endorses C5-blockers as the initial treatment for severe renal thrombotic microangiopathy (TMA). This retrospective, single-center study reports a series of 7 patients treated with a plasmapheresis-free approach.