The present pharmacokinetic study was designed to investigate the possible interaction between valproic acid (VPA) and ethosuximide (ESM) in humans. Six drug-free healthy volunteers, four men and two women, 18-42 years of age, received a single oral dose of 500 mg ESM before and during a treatment with VPA at 800- to 1,600-mg daily doses. The second ESM dose was given 9 days after VPA administration was started. In this latter condition, a significant (p less than 0.05) increase in ESM serum half-life, from 44 to 54 h on average, and a significant (p less than 0.05) decrease in total body clearance, from 11.2 to 9.5 ml/min on average, were observed. Other pharmacokinetic parameters were unchanged and showed values similar to those reported in the literature. Serum VPA levels ranged between 66.8 and 95 micrograms/ml. Two subjects showed no evidence of interaction. Although a great interindividual variability in the occurrence of VPA-ESM interaction can be observed, the present study indicates that VPA is able to inhibit the metabolism of ESM. Possible factors affecting this interaction are hypothesized and discussed.