Phenobarbital has been observed clinically to alter the metabolism of meperidine, with resultant enhanced toxicity. In order to determine if this effect occurs consistently, 12 health volunteers were entered into a two-way, crossover study comparing the pharmacokinetics and metabolism of meperidine after pretreatment with both phenobarbital and placebo. Phenobarbital pretreatment had no significant effect on serum levels or the half-life of meperidine. However, phenobarbital pretreatment resulted in a decrease in the cumulative excretion of meperidine and an increase in the cumulative excretion of the N-demethylated metabolite normeperidine. Similarly, phenobarbital pretreatment resulted in a decrease in meperidinic acid and increase in normeperidinic acid. In addition, phenobarbital pretreatment also significantly altered the hepatic clearance of meperidine, indicating an increase in the hepatic N-demethylation of meperidine. Since normeperidine has been reported to be less efficacious and more toxic than meperidine, this reported interaction may be important clinically, especially with repeated doses.