Introduction: The application of C3d and C4d as a diagnostic adjunct in the cases of inflammatory skin disease has been rarely reported in the literature. The purpose of our study is to define the significance of C3d and C4d deposition by an immunohistochemistry (IHC) on paraffin-embedded, formalin-fixed tissue as a correlative diagnostic adjunct in the assessment of inflammatory skin disease. Objective: To evaluate use of C3d and C4d by immunohistochemistry (IHC) on formalin-fixed tissue as diagnostic adjunct in the various inflammatory skin diseases. Method: 1) Diagnosed cases of inflammatory skin diseases on histology were selected for the study. 2) H&E slides were studied for morphological assessment. 3) IHC makers for C3d and C4d were performed on the paraffin blocks using C3d and C4d- antibody based detection kits. Result: 100% cases of DLE & SLE were positive for deposition of C3d & C4d at dermo-epidermal junction. 100% cases of Bullous Pemphigoid & 57% of cases of Bullous Pemphigoid were positive for C3d and C4d deposition respectively at dermo-epidermal junction. 100% cases of Behçet's disease & 42% cases ofLeukocytoclastic Vasculitis were positive for deposition of C3d & C4d in blood vessel. Conclusion: The C3d and C4d assays define an important diagnostic adjunct in the evaluation of collagen vascular disease, cutaneous vascular disease, and autoimmune vesiculobullous disease. The assays may prompt further DIF testing or, in some instances, may even define a reasonable substitute for DIF and/or add to the morphologic assessment of a biopsy specimen submitted for routine light microscopic assessment.