The present study was undertaken to investigate the effect of an n-hexane extract of Myristica fragrans seeds on depression in mice by using the forced swim test (FST) and the tail suspension test (TST). M. fragrans extract (5, 10, and 20 mg/kg) was administered orally for 3 successive days to different groups of Swiss male young albino mice. M. fragrans extract significantly decreased immobility periods of mice in both the FST and the TST. The 10 mg/kg dose was found to be most potent, as indicated by the greatest decrease in the immobility period compared with the control. Furthermore, this dose of the extract was found to have comparable potency to imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.). The extract did not have a significant effect on locomotor activity of mice. Prazosin (62.5 microg/kg i.p.; an alpha (1)-adrenoceptor antagonist), sulpiride (50 mg/kg i.p.; a selective D(2) receptor antagonist), and p-chlorophenylalanine (100 mg/kg i.p.; an inhibitor of serotonin synthesis) significantly attenuated the M. fragrans extract-induced antidepressant-like effect in the TST. Thus, extract of M. fragrans elicited a significant antidepressant-like effect in mice, when assessed in both the TST and the FST. The antidepressant-like effect of the extract seems to be mediated by interaction with the adrenergic, dopaminergic, and serotonergic systems.