We determined oncotic pressure (pi) by membrane osmometry and assayed total protein (TP) and albumin (Alb) concentrations in plasma of 102 nephrotic subjects and 27 healthy controls. All three quantities were markedly depressed in the nephrotic group. When plasma was serially diluted and concentrated, nephrotic but not control plasma also exhibited a highly variable change point in the nonlinear relationship between TP or Alb and pi. Absent a unique change point, we developed quadratic models which incorporated TP, Alb, and (TP x Alb) to prospectively predict pi in unperturbed plasma. The ability of the most successful quadratic model to predict pi in afferent or efferent arteriolar plasma was limited; the prediction errors reached 10 mmHg in nephrotic and 6 mmHg in control subjects. The nephrotic model coefficients also differed significantly from control and pointed to an important influence of nonalbumin proteins on pi in nephrotic plasma. Investigation of the intrinsic membrane properties of diseased glomerular capillary walls requires precise knowledge of pi. For this purpose we recommend that pi be directly determined by membrane osmometry rather than calculated from protein concentration(s).