We reexamined the efficacy of the clinically effective anticonvulsant drug phenytoin in the kindling model. We investigated the effects of varying doses of intravenous phenytoin on serum concentrations and on several indexes of stimulation-evoked kindled seizures. Intravenous phenytoin produced a dose-dependent increase in serum phenytoin concentration and powerfully suppressed both limbic and clonic motor seizures. Although focal afterdischarge threshold was elevated to some extent, the most profound effect of phenytoin was limitation of seizure propagation. Variable and low serum concentrations of intraperitoneal or oral phenytoin may explain previous findings that phenytoin is only partly effective or ineffective against kindled seizures. Together with previous results with other drugs, the excellent correlation among drugs effective against human and kindled seizures strengthens the validity of this model. We suggest that the efficacy of experimental anticonvulsant drugs be established in the kindling model before initiation of clinical trials for partial and secondarily generalized seizures.