Objectives/Hypothesis: The aim of this study was to investigate possible interactions between grapefruit juice and montelukast for up to 4 hours. Study Design: A prospective, crossover study with 23 healthy volunteers was performed in two sessions. Methods: In the first session, volunteers were treated with oral montelukast 10 mg once daily with 250 ml water. After a 10-day washout period, the same volunteers were treated with 10 mg montelukast with 250 ml grapefruit juice. Blood samples were collected 2, 3, and 4 hours after drug administration and kept at 80 degrees C after both applications. Plasma samples were analyzed for montelukast concentration. Results: The mean plasma concentration of montelukast across all time intervals was significantly greater (P = 0.0001) for those given grapefruit juice (517, 484, and 440) versus those treated with water (366, 356, and 292). Moreover, with respect to the time the sample was collected, there was no significant difference (P = 0.13) in the mean total plasma concentration up to 4 hours after montelukast ingestion for either group. There was a significant difference between the groups according to the area under curve with regard to marginal and cumulative values for all different time intervals (P < 0.05). Conclusions: Plasma concentration of montelukast was higher when administered with grapefruit juice, as compared to with water. This may have been due to the effect of grapefruit on liver metabolism of montelukast and the cytochrome P450 system.