The interaction between valproic acid (VPA) and phenytoin (DPH) was examined during therapeutic monitoring in an epileptic outpatient population. Gas-liquid chromatographic methods were used to measure DPH and VPA concentrations. (1) In 12 patients on stable DPH regimens, the mean DPH level declined from 19.7 to 15.3 μg/ml when VPA was added (p < 0.001). (2) In 20 patients receiving DPH and VPA, the median free fraction was 15.8%, compared to 9.1% free DPH in 40 patients receiving DPH only or DPH and phenobarbital (p < 0.001). (3) Addition of VPA to a stable DPH regimen may result in a transient increased risk of DPH toxicity, followed by restabilization at the original free DPH level.