Plasma protein binding of phenytoin (diphenylhydantoin) in 63 epileptic patients was investigated with an ultrafiltration technique at room temperature using14C-labelled phenytoin. A strong correlation was found between the total and the unbound drug concentration (r = 0.97, p < 0.001). The unbound phenytoin fraction was 7.1 ± 1.0% with a range of 4.9 to 10.2%. This variation is considerably less than that reported recently by different authors. Individual phenytoin binding was reproducible when the determination was repeated several weeks later. Salivary phenytoin concentrations in 33 epileptic patients were significantly correlated to the unbound (r = 0.83) and total concentrations (r = 0.82) of phenytoin in plasma. This study confirms that the clinical practice of monitoring total phenytoin plasma concentrations is sufficient, since the unbound phenytoin fraction has only a 2-fold interindividual variation in epileptic patients, provided that they do not suffer from renal or hepatic disease.