Post-streptococcal glomerulonephritis (PSGN) is an immune-mediated complication associated with preceding group A streptococcal (GAS) skin or throat infections. PSGN constitutes a significant risk factor for chronic kidney disease. The pathogenesis of PSGN is considered multifactorial and remains incompletely understood; however, it predominantly involves immune-complex mediated glomerular damage triggered by nephritis-associated GAS antigens. Although streptococcal pyrogenic exotoxin B (SpeB) and nephritis associated plasmin receptor (NAPlr) are identified nephritogenic antigens, sero-epidemiological studies suggest an association between streptococcal inhibitor of complement (SIC) and PSGN, but the precise role of SIC in PSGN remains unclear. To address this, Lewis rats were exposed twice to SIC protein over ~60 days via a combination of subcutaneous injection with complete Freund’s adjuvant (CFA) and/or subcutaneous implantation of mini-osmotic pumps. Urine samples were collected weekly until euthanasia, after which post-mortem blood and kidney samples were obtained for biochemical and histopathological analyses. Although SIC-specific antibodies developed in the SIC-treated rats, no significant functional or histological changes in the kidneys were observed, suggesting that SIC may not by itself contribute to the development of PSGN. To explore potential synergistic factors associated with SIC in the pathogenesis of PSGN, our current studies involve exposing Lewis rats to subcutaneous injection of a purified SIC with either SpeB or NAPlr emulsified in CFA, followed by three booster injections of the same combination emulsified in incomplete Freund’s adjuvant over two months. In these studies, we will determine the contribution of SIC in combination with SpeB and/or NAPlr in the development of PSGN.