The effect of long-term phenytoin therapy on the immune response to inactivated influenza vaccine was evaluated. The patients were 31 white men who were receiving long-term phenytoin therapy for seizure disorders and 31 age-matched controls. Prevaccination blood samples were collected, and the patients were vaccinated subcutaneously with 0.5-mL inactivated whole-virion trivalent influenza vaccine. Venous blood samples were collected at 2, 4, 6, 9, 12, and 24 weeks after vaccination and stored at -20 degrees C until analysis. Total serum phenytoin concentrations were measured by fluorescence polarization immunoassay. Immune response was measured by assaying the sera for hemagglutinin-inhibiting antibody to each of the three antigenic strains. Seroconversion was defined as a fourfold or greater increase in serum antibody titer following vaccination. In the phenytoin-treated patients, the mean (+/- S.D.) serum phenytoin concentration before vaccination was 9.9 +/- 6.1 micrograms/mL. Prevaccination geometric mean titers were high enough in both groups to indicate that these patients had been exposed to these or related antigens, and medical records confirmed that some of the patients had been vaccinated the year before. The percent of patients demonstrating seroconversion to each antigen at week 4 was low in both groups, and there were no significant differences between the two groups. The cumulative seroconversion responses observed up to week 24 were also not significantly different. Long-term phenytoin therapy should not affect the efficacy of influenza vaccine in patients who have been previously exposed to infection or vaccination with identical or related strains.