Fluoxetine (Prozac) produces sexual dysfunction in a substantial number of patients. In the few animal studies designed to address this sexual dysfunction in females, data have been inconsistent. Some investigators report that the drug disrupts sexual behavior without affecting the estrous cycle while we have reported robust effects of fluoxetine on the estrous cycle. The current studies were designed to initiate examination of procedural differences that may account for these contradictory outcomes. In the first experiment, intact, regularly cycling female rats were injected daily for 10 days with 10 mg/kg fluoxetine (intraperitoneally) or vehicle. Male-exposed, fluoxetine- or vehicle-treated rats were housed in a room with males and placed for 5 min/day into a male's cage. Other fluoxetine-treated females were housed in a room separate from males. In the second experiment, this protocol was repeated for 20 days and an additional group of females were exposed to male bedding for 5 min/day. Without male exposure, fluoxetine rapidly disrupted vaginal estrus and sexual receptivity so that approximately 50% of the rats failed to show vaginal estrus during the first 5 days; and the majority of the rats had a blocked cycle by 10 days of treatment. With male exposure, these reproductive effects were attenuated. The majority of rats cycled normally during the first 5 days of treatment and more than half cycled throughout the experiment. Loss of behavioral receptivity occurred even when normal estrous cyclicity was present. Although exposure to the male's bedding may have delayed the onset of estrous cycle disruption, five min daily exposure to a male's bedding did not prevent the disruptive effects of fluoxetine. These findings are consistent with evidence that fluoxetine's effect on female sexual dysfunction may result, in part, from the drugs' disruption of the hypothalamic-pituitary-gonadal axis. However, the data also evidence dissociation between the effects of fluoxetine on vaginal and behavioral estrus. These findings may also explain why different laboratories have reported the presence or absence of estrous cycle disturbances following daily treatment with fluoxetine.