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INTRODUCTION: C4D is a well-known biomarker of complement cascade. The utility of C4D in identification of antibody-mediated rejection has been known since its incorporation in Banff classification in 2003. Recently, many researchers have turned their attention to C4D deposition in native renal diseases. The present study was done at our tertiary care center to adjudge the significance of C4D deposits in native renal diseases across Indian cohort of patients. MATERIALS AND METHODS: A retrospective study was done on fifty cases of native renal diseases and followed up at 6 months. C4D immunohistochemical analysis was performed on formalin-fixed paraffin-embedded renal tissue sections with antibody against C4D (polyclonal rabbit immunoglobulin G antihuman C4D antibody). RESULTS: All cases of membranous nephropathy, immunoglobulin A nephropathy, and hypertensive nephropathy showed glomerular C4D positivity ranging from 2+ to 3+. Nearly 50%, 50%, 43%, and 40% cases of diabetic nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and postinfectious glomerulonephritis, respectively, demonstrated positive glomerular C4D deposits. Increased intensity expression of glomerular C4D deposits was in significant concordance with presenting 24 h urinary protein level at the time of biopsy and in follow-up trends; C4D positive cases were noted to have slowed recovery process as evidenced by delay in returning to normal range proteinuria. Higher histological grades in respective native diseases' classification correlated with increased glomerular C4D intensity expression. C4D positivity in other renal compartments did not yield any significant results. CONCLUSION: C4D positivity can be explored as a diagnostic and prognostic tool in native renal diseases as well, apart from transplant biopsies' evaluation