The interaction between valproic acid (VPA) and phenytoin (DPH) was examined during therapeutic monitoring in an epileptic outpatient population. GLC methods were used to measure DPH and VPA concentrations. In 12 patients on stable DPH regimens, the mean DPH level declined from 19.7 to 15.3 .mu.g/ml when VPA was added (P < 0.001). 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). Addition of VPA to a stable DPH regimen may cause a transient increased risk of DPH toxicity, followed by restabilization at the original free DPH level.