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Background: Glomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN., Study Design: Systematic review and meta-analysis., Setting & Population: Patients with biopsy-proven primary IgAN without age limitations.Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression., Predictor: Glomerular C4d deposition., Outcome: Composite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease., Results: 12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity ( I 2  < 0.001). Patients with C4d deposition had lower estimated glomerular filtration rates (mean difference [MD], -11.48; 95% CI, -18.27 to -4.70; P  < 0.001). Patients with C4d deposition had lower estimated glomerular filtration rates (mean difference [MD], -11.48; 95% CI, -18.27 to -4.70; P  < 0.001) as well as higher urinary protein-creatinine ratios (MD, 0.87; 95% CI, 0.53-1.21; P  < 0.001) or 24-hour urinary protein excretion (MD, 0.99; 95% CI, 0.50-1.47; P  = 0.02) than patients without C4d deposition. Glomerular C4d deposition was associated with a high Oxford classification score, including M1, E1, S1, and T1/2 lesions (all P  ≤ 0.006). Patients with C4d deposition had higher rates of use of renin-angiotensin system blockers and immunosuppressants. Glomerular C4d was found to be a risk factor for the composite kidney event (RR, 3.17; 95% CI, 2.29-4.40; P  ≤ 0.006). Patients with C4d deposition had higher rates of use of renin-angiotensin system blockers and immunosuppressants. Glomerular C4d was found to be a risk factor for the composite kidney event (RR, 3.17; 95% CI, 2.29-4.40; P  < 0.001; adjusted HR, 2.05; 95% CI, 1.53-2.76; P  < 0.001) and end-stage kidney disease (RR, 4.37; 95% CI, 3.15-6.07; P  < 0.001) without evidence of heterogeneity., Limitations: The definition of positive C4d was not uniform and not all studies provided data about kidney outcomes., Conclusions: Glomerular C4d deposition is associated with an adverse prognosis and may be a useful biomarker of disease prediction in IgAN., (© 2021 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)