BACKGROUND Immunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. Complement activation is involved in the disease. However, the clinical significance of C4 deposition in IgAN is obscure. METHODS A multicenter retrospective study was conducted in biopsy-proven IgAN patients. Based on mesangial C4 deposition, patients were divided into two groups. The baseline clinical data and immunopathological phenotypes were compared. The composite endpoint was defined as eGFR decline greater than 50%, doubling of baseline serum creatinine, the occurrence of end-stage renal disease (ESRD). RESULTS A total of 642 IgAN patients were recruited, with 41 patients showing mesangial C4 deposition. The mesangial C4 positive group showed lower serum albumin, higher proteinuria, and a higher rate of IgG, IgM, and C1q mesangial deposition. After a median follow-up of 43.18 months, 81 (12.62%) patients achieved the composite endpoint. The multivariate Cox regression models identified glomerular C4 deposition (hazard ratios [HR] = 3.22, 95% confidence intervals [CI] = 1.51-6.87, p < 0.01), global sclerosis (G1 vs. G0, HR = 1.90, 95%CI = 1.02-3.52, p = 0.04; G2 vs. G0, HR = 3.72, 95%CI = 1.98-7.00, p < 0.01), male (HR = 1.80, 95%CI = 1.10-2.97, p = 0.02), serum creatinine (HR = 1.01, 95%CI = 1.00-1.01, p < 0.01), triglyceride (HR = 1.17, 95%CI = 1.01-1.35, p = 0.04), proteinuria (HR = 1.07, 95%CI = 1.01-1.13, p = 0.02), serum C3 level (HR = 0.05, 95%CI = 0.01-0.25, p < 0.01), and serum C4 level (HR = 99.59, 95%CI = 8.69-1140.89, p < 0.01) as independent risk factors for poor renal outcomes. CONCLUSIONS Glomerular mesangial C4 deposition and global sclerosis are independent predictors for poor prognosis in IgAN patients.