This study was conducted to determine the relative rectal bioavailability of fluoxetine capsules as well as the acceptability of the rectal route of fluoxetine capsule administration. Using a 2-period, crossover design with a 30-day washout between study sessions, 20 mg fluoxetine capsules were administered to 7 healthy, drug-free, nonsmoking volunteers by the oral and rectal routes. Blood samples were collected at baseline, and 1, 2, 4, 6, 8, 10, 12, 24 hours, as well as 2, 3, 4, 5, 7, 14, 21, 28 days following drug administration. Plasma concentrations of fluoxetine and norfluoxetine were determined using high performance liquid chromatography with ultraviolet detection. The area under the plasma concentration versus time curve could not be determined for fluoxetine following rectal administration due to very low fluoxetine plasma levels. The relative rectal bioavailability was determined for norfluoxetine and total (fluoxetine + norfluoxetine) in each individual. Six subjects completed both phases of the study. The relative bioavailability of rectally administered fluoxetine was approximately 15% [norfluoxetine, 95% CI 9-21%, and total (fluoxetine + norfluoxetine), 95% CI 8-22%]. The rectal route of administration was rated as reasonably tolerable by all subjects. Although rectal bioavailability of fluoxetine capsules is considerably less than oral, the rectal route of administration might be an option in patients who cannot take oral medications.