The present study investigated the probable protective role of vitamin C in alleviating 5-fluorouracil (5-Fu)-induced nephrotoxicity in male mice (Mus musculus). Thirty male CD-1 mice were equally divided into three groups: Group I (the control group), received 0.9% NaCl; group II, received intraperitoneally (i.p.) 80 mg of 5-Fu/kg body weight (b.wt)/day for four weeks; group III, received (i.p.) 80 mg of 5-Fu plus 12 mg of vitamin C/kg b.wt/day for four weeks. Animals of all groups were killed at the end of the experiment, and the renal tissue samples were taken and processed for light and electron microscopical examinations. Light microscopic observations revealed that administration of 5-Fu caused erosion of the parietal cells of Bowman's capsules, widening of the urinary spaces, and disruption of the glomerular capillaries and hemorrhage. The cells of the proximal and distal tubules exhibited vacuolar degeneration and coagulative necrosis. The nuclei of these cells manifested pyknosis and karyolysis. Ultrastructural examination revealed damage of the parietal epithelium of Bowman's capsules with fusion and destruction of the foot processes of the podocytes. The cells of the proximal tubules displayed destruction of the microvilli constituting the brush borders and degeneration of the mitochondria. The distal tubules displayed destruction of both the basal infoldings and the mitochondria with fragmentation of the rough endoplasmic reticulum. Histological and ultrastructural results revealed that the treatment with vitamin C simultaneously with 5-Fu led to apparent protection of the renal tissue. This might suggest that vitamin C has a protective potential against 5-Fu-induced nephrotoxicity.