High dietary salt is common in western countries and is an important contributor to increased cardiovascular disease. Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) is an essential function of the renal microcirculation, which could be affected by excessive dietary salt. High salt (HS) increases renal reactive oxygen species (ROS) generation partly by the enzyme NADPH oxidase. We hypothesized that a HS diet would impair autoregulation via NADPH oxidase-dependent ROS generation. The role of NADPH-dependent ROS production on the blunted autoregulatory response with a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. The increase in renal lipid peroxidation and p67^phox expression induced by HS was prevented by apocynin treatment. Control afferent arterioles exhibited normal autoregulatory behavior in response to acute increases in renal perfusion pressure (RPP), whereas arterioles from HS rats exhibited a blunted response. Autoregulatory behavior in HS rats was restored in vitro by acute exposure to the NADPH oxidase inhibitor, apocynin. At the whole kidney level, in vivo studies showed RBF and GFR both declined in HS rats when left kidney RPP was reduced from ambient to 95 mmHg whereas control rats maintained stable GFR and RBF consistent with efficient autoregulatory behavior. Apocynin treatment improved in vivo autoregulatory behavior in HS rats and had no detectable effect in normal salt fed rats. These data support the hypothesis that impaired renal autoregulatory behavior in rats fed a HS diet is mediated by NADPH-oxidase-derived ROS.