The protein binding of carbamazepine (CBZ) in vitro was assessed in sera from 47 patients with various diseases known to alter alpha 1-acid glycoprotein (AAG) concentration and from 20 drug-free normal control subjects. In the patient group, AAG and albumin (HSA) concentrations ranged from 6 to 74 mumol/l and from 377 to 652 mumol/l, respectively; in the controls, protein concentrations were less variable, ranging from 11 to 26 mumol/l for AAG and from 623 to 754 mumol/l for HSA. In both the patient and the combined patient and control groups, free CBZ fractions were inversely correlated with the serum AAG concentration (r = -0.62). No significant relationship could be found between the free CBZ fraction and the serum HSA concentration. The free CBZ fraction was moderately but significantly decreased in patients with AAG levels above 26 mumol/l (the highest value found in controls) as compared either to patients with a normal AAG concentration or to control subjects (19 +/- 5% vs 23 +/- 4% and 23 +/- 2%), despite the finding of a higher HSA concentration in the control group. The data confirm AAG as an important determinant of interindividual variability in serum CBZ binding.