Background: C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement-targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV-104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. Objectives and Methods: We evaluated the ability of CPV-104 to antagonize NeF-mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid-phase assays in which C3bBb decay and formation were assessed in the presence of CPV-104 or serum-derived FH (sd-FH). The impact of CPV-104 ex vivo was tested in fluid-phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. Results: CPV-104 accelerated decay of NeF-stabilized C3bBb with efficacy comparable to sd-FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV-104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV-104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd-FH. In fluid-phase assays, using patient sera, CPV-104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd-FH across patient samples. Conclusions: CPV-104 effectively limits both stabilization and formation of AP C3 convertases in NeF-positive C3G, demonstrating superior functional activity compared with sd-FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV-104 represents a promising and potentially safer therapeutic strategy for NeF-driven C3G and warrants further clinical investigation.