5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5 FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: Control group; L-arginine group ; 5-FU group and L-arginine for one week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with H&E, Masson's Trichome and PAS stains. Immunohistochemical demonstration of caspase-3 for apoptosis and inducible nitric oxide synthase (iNOS). Image analyzer was used to analyze the results morphometrically and statisticaly analyzed. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney / body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis.