The sequence of changes in renal function in endotoxemic acute renal failure (ARF) and the role of hypotension and systemic hemodynamics were evaluated in awake female Sprague-Dawley rats given an intravenous bolus of Escherichia coli endotoxin (20-40 mg/kg). After endotoxin ARF was abrupt in onset as glomerular filtration rate (GFR) fell promptly and progressively by 53% within 3.5 h, whereas renal blood flow decreased by 42% and renal vascular resistance nearly doubled. Systemic hemodynamics remained stable, including mean arterial blood pressure, cardiac output, and total peripheral resistance. Early endotoxemic ARF was associated with oliguria and sodium retention, a finding consistent with intact tubular function. Three and one-half hours after endotoxin, however, fractional water and sodium excretion were significantly increased. Ultrastructural studies then demonstrated sequestration of phagocytic leukocytes and intracellular edema in the peritubular capillaries with normal glomeruli. The decrease in GFR was spontaneously reversible within 7-9 days. Extracellular fluid volume expansion with saline either before or 24 h after administration of endotoxin failed to prevent the decrease in GFR or to normalize renal function. The data suggest that endotoxin has direct renal effects. The endothelial cells may be the primary target of endotoxin in the kidney.