We have analyzed the efficiency with which p-amino-hippuric acid (PAH) is extracted (EPAH) by patients with healthy kidneys (n = 13) or kidneys damaged by chronic cyclosporin nephropathy (n = 21) or primary glomerulopathy (n = 12); respective values (mean +/- SE) for EPAH were 0.87 +/- 0.03, 0.77 +/- 0.03, and 0.69 +/- 0.04. Judged by a 131I-hippuran-to-PAH clearance ratio of 0.75 +/- 0.05, extraction ratio of hippuran was less efficient than EPAH in three glomerulopathic patients. A direct relationship was defined between EPAH and glomerular filtration rate (GFR) (r = 0.54) or calculated efferent oncotic pressure (IIE; r = 0.41, P less than 0.01). Curve fitting by means of quadratic spline functions revealed GFR and IIE to be additive in predicting EPAH (R2 = 0.45). Linear model prediction methods and a sample reuse technique failed to predict EPAH reliably from GFR and preglomerular oncotic pressure (IIA); however, 95% prediction intervals exceed 0.30 EPAH units in width. We conclude that oncotic pressure (presumably reflecting albumin concentration) along with GFR is predictive of EPAH depression in humans with chronic renal disease. However, even sophisticated curve-fitting techniques are too imprecise for accurate prediction of EPAH in a given individual. We submit that renal venous sampling to determine EPAH continues to be necessary for the accurate determination of the rate of plasma flow in the injured human kidney.