Abstract: This case report details the efficacy of eculizumab in treating refractory focal segmental glomerulosclerosis (FSGS) complicated by eosinophilic granulomatosis with polyangiitis (EGPA). A middle-aged male presented with nephrotic syndrome, which progressed to FSGS several years later. Despite conventional immunosuppressive regimens (including corticosteroids, calcineurin inhibitors, and rituximab), persistent massive proteinuria (24-hour urine protein > 10.00 g) remained. Based on robust evidence of terminal complement pathway activation (C5b-9 level: 317.56 ng·mL^-1, exceeding the upper limit by 30%) and features of glomerular endothelial injury, the patient received targeted therapy with eculizumab to block C5 cleavage (inhibiting the common terminal step of the classical, lectin, and alternative pathways). The dosing regimen comprised: an induction phase (900 mg weekly for 4 weeks) followed by a maintenance phase (900 mg every 2 weeks for 2 weeks; with slight variations in intervals based on clinical status; cumulative dose: 8 100 mg), combined with low-dose prednisone (20 mg·d^-1) to control T helper cell 2 (Th2)-driven inflammation. After 4 weeks of treatment, the patient achieved an 83.65% reduction in 24-hour urine protein (from 16.27 g to 2.66 g), normalization of serum creatinine (decreased from 166 μmol·L^-1 to 80 μmol·L^-1), and a 139.66% increase in estimated glomerular filtration rate eGFR，from 41.1 mL·min^-1·(1.73 m²)^-1 to 98.5 mL·min^-1·(1.73 m²)^-1. Complement activation markers and inflammatory cytokines were significantly reduced. The results indicate that targeted blockade of complement C5 with eculizumab can effectively reverse FSGS-associated renal injury, offering a new therapeutic direction for patients who are refractory to conventional treatment. Comprehensive risk management, including anticoagulation, infection prophylaxis, and renal protective medications, was implemented throughout the treatment course, providing valuable insights for multidimensional management of complex nephropathy.