Background <p>IgA nephropathy is a disease with a highly variable natural history, for which there is an increasing understanding of the role of complement activation in its pathogenesis and progression. We aimed to assess the clinical and prognostic implications of C4d staining in the kidney biopsy of IgA nephropathy patients.</p> Methods <p>This was a retrospective observational study wherein the medical records of IgA nephropathy patients were reviewed and baseline characteristics, kidney biopsy findings, treatment response and follow-up data were noted. We aimed to estimate the prevalence of C4d staining and assess its correlation with clinical presentation, MEST-C scoring as well as its predictive value on renal outcomes.</p> Results <p>A total of 131 kidney biopsies were studied in which the prevalence of C4d staining was 63.36%. C4d positivity was significantly associated with hypertension (<i>P</i> = 0.005), greater degree of proteinuria (<i>P</i> = 0.013) and lower estimated glomerular filtration rate (eGFR) (<i>P</i> = 0.04) at presentation. MEST-C score analysis revealed significant association of Segmental sclerosis (S1), Tubular atrophy and Interstitial Fibrosis (T1, T2) and a greater degree of glomerulosclerosis with C4d staining (<i>P</i> value &lt; 0.001). On follow-up, lesser rates of complete remission, higher serum creatinine and lower eGFR were seen in the C4d positive group (<i>P</i> &lt; 0.001). C4d positivity independently predicted progression to kidney failure [HR: 2.42; 95% CI:1.11–5.26 (<i>P</i> = 0.026)] with 5-year kidney survival of 58% (<i>P</i> &lt; 0.001).</p> Conclusion <p>Mesangial C4d deposition is associated with adverse clinical and pathological characteristics and is an independent risk factor for progression to kidney failure in patients with IgA nephropathy. Thus, C4d staining could be integrated into routine kidney biopsy analysis as a potentially useful biomarker for prognostication and targeted complement-based therapies.</p> Graphical abstract <p></p>