The effect of nefazodone on the pharmacokinetics of a single dose of phenytoin was evaluated in 18 healthy male subjects. The subjects received a single oral dose of phenytoin, 300 mg, on day 1 of the study and the pharmacokinetic profile of the drug was determined. After a washout period followed by oral administration of nefazodone, 200 mg twice daily for 7 days, subjects received a single dose of phenytoin, 300 mg concomitantly with the morning dose of nefazodone on day 12, and the pharmacokinetic profile of phenytoin was determined again. Minimum plasma concentrations of nefazodone and its main metabolites indicated that steady state had been achieved for nefazodone when phenytoin and nefazodone were administered concomitantly. No significant differences were demonstrated between mean single-dose pharmacokinetic parameters of phenytoin when administered alone on day 1 and concomitantly with nefazodone on day 12. Assessment of adverse events, clinical laboratory parameters, electrocardiograms, vital signs, and physical examinations indicated that concomitant administration of nefazodone and phenytoin was safe and well tolerated. These data demonstrate that nefazodone does not affect the single-dose pharmacokinetics of phenytoin, but do not preclude the possibility of such an interaction when phenytoin is administered on a long-term basis. A clinically significant interaction between nefazodone and phenytoin through a pharmacokinetic mechanism is unlikely.