The plasma protein binding of diazepam and lidocaine was measured in patients with renal disease (those with uremia, nephrotic syndrome, or who had received a transplant) and in age- and sex- matched control subjects. Percentage unbound diazepam in plasma was increased over control in all three groups of patients as follows: uremic patients 3.23%, control, 1.64% (P less than 0.001), nephrotic patients, 3.55%, control, 1.63% (P less than 0.001); and transplant recipients, 2.11%, control 1.50% (P less than 0.001). The binding ratio (molar concentration of bound to unbound drug) in patients was related to albumin concentration (r = 0.609, P less than 0.001). Percentage of unbound lidocaine did not differ substantially from control in nephrotic patients (34.2%, control 30.8%), but was reduced in the uremic patients (20.8%, control 30.7%, P less than 0.001) and transplant recipients (24.6%, control 33.7%, P less than 0.005). These increases were associated with increases in alpha 1-acid glycoprotein (AAG) concentration (uremic patients 134.9 mg/dl, control 66.3, P less than 0.001; transplant recipients 106.5, control 65.6, P less than 0.001). The binding ratio of lidocaine was closely related to the AAG concentration in patients (r = 0.933, P less than 0.001) and controls (r = 0.719, P less than 0.001). Thus, the binding of basic drugs may be increased or decreased in patients with renal disease, depending on the relative contribution of the individual plasma to the total binding and the type of disease.