The objective of this study was to investigate the sex-dependent kidney morphology of male and female guinea pigs using light microscope and different immunohistochemistry techniques. Hamatoxyline and Eosin (H&E) and Periodic Acid Schiff (PAS) staining techniques were performed for the general histological observations. Immunohistrochemistry was performed to detect renin positive site, expression of Cyclo-oxygenase -2 (COX-2) and Nitric Oxide Syntheses (nNOS), Number of renin, COX-2, and nNOS positive sites were counted and tabulated. Both Light microscopic examination and immuno-histochemical study reveals distinct differences between the male and female kidneys. Parietal layer of Bowman's capsule was consisted of a single layer of simple squamus epithelium in female, but in male, it was composed of a single layer of simple cuboidal epithelium. PAS-positive brush border and vacuoles of different shapes and sizes were appeared in the proximal straight tubules (PST) and collecting ducts in female guinea pig. Whereas in male, vacuoles were not detected in the PST epithelium and collecting ducts. Strong staining intensity for PAS-positive brush border in the PST and collecting ducts was observed in the outer medulla of female guinea pig kidney, but the reaction was observed poor in male. Neural Nitric Oxide Synthase (nNOS)-positive reaction was observed in PST epithelium and collecting ducts in female kidney, but male kidney revealed nNOS-negative reaction for PST and collecting ducts. Renin, COX-2 and nNOS-positive sites were detected in the juxtaglomerular cells (JGCs) cells and macula densa cells of both male and female kidneys. When counted, total numbers of glomeruli, renin, COX-2, and nNOS positive-sites were higher in female, when compared to that of the male. However, number of glomeruli, areas of renin, COX-2 and nNOS-positive sites reveals no significant differences between male and female species (P<0.05).