Fluoxetine produces initial paradoxical anxiogenic effect in some patients. In an elevated plus-maze (EPM), fluoxetine triggers an anxiogenic-like effect in rodents. Behavioral responses to psychoactive drugs can be modified by the pineal gland. We assessed the actions of fluoxetine in the EPM in melatonin-proficient C3H mice, melatonin-deficient C57BL6 mice, and in sham-operated and pinealectomized mice. Mice were assayed 30 min after the first injection and on day 14. Protracted fluoxetine treatment reduced the time on the anxiogenic open arms and increased the entries into the safe closed arms in sham-operated C3H mice. Fluoxetine was ineffective in pinealectomized C3H or C57BL6 mice. It is possible that the pineal system contributes to the previously observed anxiogenic action of fluoxetine in humans.