We have previously found that lysine produces acute renal failure in rats. To define the acute effects of lysine, rats given lysine at 8.9 mg/kg/min, i.v. for 4.5 hr were compared with control rats receiving equiosmolar dextrose. Systemic blood pressure was stable in both groups. Mean intratubular pressure, inulin clearance (CIn), and renal blood flow were determined at 45-min intervals. Intratubular pressures measured with a servonulling micropressure device were elevated by 90 min in lysine-treated animals, with tubular heterogeneity, while pressures in dextrose-treated rats were normal and homogeneous. By 135 min CIn in lysine-treated rats was 45% of CIn in dextrose rats. Urine output fell in lysine-treated rats. Renal blood flow determined by flow probe remained normal in lysine-treated rats through 135 min and did not decline significantly until 180 min. Significant dilatation of surface tubules was documented by intravital microscopy beginning at 90 min in lysine-treated rats. The sequence of elevated intratubular pressure and tubular dilatation, followed by decreased CIn, and then by decreased renal blood flow suggests that lysine produces acute renal failure primarily through tubular obstruction. The tubular obstruction is followed later by an increase in renal vascular resistance.