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. All patients presented with severe renal TMA symptoms and low French score and received prompt 900mg eculizumab within a median of 9 hours from admission. Hematological recovery was rapid, and renal function improved in 6 patients within 6.5 days, with a median hospital stay of 16 days. No rescue plasmapheresis was used. We report 7 cases of an early C5-blocker and plasmapheresis-free strategy in severe renal TMA suspicious for CM-HUS, demonstrating promising initial results. Clinical trials are needed to confirm the efficacy and safety of this approach. Addressing the high cost of C5-blocking therapies and exploring cost-effective alternatives is also crucial for broader implementation and accessibility in targeted therapies for adult renal TMA.