Ischemia/reperfusion (IR)-induced nephrotoxicity is associated with proteinuria. There are also some reports about the involvement of iNOS (inducible form of nitric oxide synthase) in proteinuria associated with renal disease. The present study was designed to investigate the effect of L-Nil (N6-(1-Iminoethyl)-L- lysine hydrochloride), a selective inhibitor of iNOS, in prevention of renal proteinuria in IR injury. Ischemia was induced by 40-min clamping of the renal arteries followed by 6 h reperfusion. Rats were administered either L-Nil (3 mg/kg i.v. bolus followed by infusion of 1 mg/kg/h) or saline. To monitor glomerular 7:29 AM tubular functional changes before and after treatment, BUN, plasma creatinine Cr) and urinary NAG N-Acetyl-β-D-glucosaminidase) activity were measured. Total protein, albumin, low and high molecular weight protein excretion rates were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urine samples. Kidney ultrastructure was examined through a transmission electron microscope (TEM). Renal IR resulted in significant low and high molecular weight proteinuria. L-Nil significantly ameliorates the IR-induced increases in total protein, albumin and α1-microglobulin excretion. TEM showed loss of microvilli of the proximal tubule cells, injured mitochondria, foamy changes in the structure of nuclear and cytoplasm in IR group but pretreatment with L-Nil reduced IR-mediated renal ultrastructureal changes & tubular proteinuria. In conclusion, iNOS is involved in IR-induced tubular proteinuria.