A combination of anti-epileptic drugs gives rise to interactions that modify their disposition kinetics. To discover the clinical relevance of such interactions it is necessary to establish their direction and magnitude. Phenytoin may interact with phenobarbital either as an inducer or an inhibitor of metabolism, depending on the length of treatment with the combination of both drugs. Data obtained in six, adult, epileptic patients treated with phenobarbital alone, and later with a phenobarbital -phenytoin combination, showed that the serum levels of the barbiturate undergo an increase during the first year of treatment with the combination therapy. From this point onwards a decrease is observed in the levels of phenobarbital, to return after about 2 years to values similar to those observed with monotherapy.