Background: Vancomycin-induced nephrotoxicity is characterized by acute tubular necrosis (ATN) or interstitial damage (ATIN). Vancomycin-resistance among Enterococci has been escalating in recent years in many countries. Linezolid (LNZ), an oxazolidinone is one of the novel drugs that promised effective therapy of infections caused by vancomycin-resistant Enterococci (VRE). Objectives: The present work aimed to experimentally compare the nephrotoxicity induced by linezolid and vancomycin (VCM) on adult albino rat both biochemically and histopathologically. Material and Methods: Thirty rats were randomly divided into three groups (10 rats each) Group (I) Control group, Group (II) LNZ group and Group (III) VCM group. To study the toxic effect of linezolid on the kidney in comparison with vancomycin. The level of serum creatinine, urea and malondialdehyde (MDA) were measured. Results: It was found in this study that VCM significantly increase serum creatinine, urea and MDA concentrations compared to the control group, and LNZ insignificantly increase serum creatinine, urea and MDA compared to the control group, with no significant difference between the effects of two drugs. Histopathological study of VCM-treated rat kidney showed marked interstitial nephritis with tubular necrosis and desquamation of tubular epithelial cells. Conclusion and Recommendations: Nephrotoxicity in linezolid-treated rats was less than vancomycin-treated rats. Further studies are needed about effect of linezolid on kidney.