We performed this study to determine if an interaction exists during the co-administration of ciprofloxacin with phenytoin. Seven healthy volunteers received oral phenytoin, 200 mg/day, as a single dose for 10 days. On day 9, phenytoin blood sampling was performed at times 0, 1, 2, 4, 6, 8, 10, 12, and 24 h. On day 10, oral ciprofloxacin, 500 mg, b.i.d. was initiated. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis was performed to determine if there were differences between the area under the concentration time curve (AUC), maximum serum concentration, Cmax, and time of maximum serum concentration, Tmax, of phenytoin before and during co-administration of ciprofloxacin. Four subjects completed the study. Results of the analysis showed no significant differences between AUC, Cmax, and Tmax of phenytoin before and during ciprofloxacin administration. However, one subject showed marked reductions in both AUC and Cmax. Similar reductions in plasma concentrations have also been reported, resulting in breakthrough seizures. In conclusion, ciprofloxacin was not shown to increase phenytoin plasma concentrations or AUC in healthy volunteers. The potential for decreasing plasma phenytoin concentrations may exist and warrants close monitoring of levels when these two agents are given simultaneously.