The present behavioural investigation evaluates the antidepressant potential of ondansetron (OND), a widely used (in management of cancer chemotherapy-induced nausea and emesis) 5-HT3 receptor antagonist. Separate groups of mice received acute or chronic treatment of OND (0.005-1000 microg/kg), and were subjected to spontaneous locomotor activity test or antidepressant assays, namely, the forced swim and tail suspension tests. Interaction studies with fluoxetine, venlafaxine, desipramine and 8-hydroxy-2-(di-n-propylamino) tetralin were conducted in the forced swim test. The effect of OND (0.01-1000 microg/kg) in combination with paroxetine (10 mg/kg, for 14 days) on the behaviour of male bulbectomized or sham-operated rats was also assessed. The postbulbectomy behavioural analysis included exploration in the open field and elevated plus maze. OND exhibited a biphasic dose-response profile, with antidepressant-like effects peaking at 0.1 microg/kg, in the forced swim and tail suspension tests. None of the tested doses influenced spontaneous locomotor activity. Chronic OND pretreatment augmented the antidepressant effects of fluoxetine and venlafaxine but did not influence the effects of desipramine or 8-hydroxy-2-(di-n-propylamino) tetralin. Chronic OND (10 microg/kg) reversed hyperactivity in the open field, and decreased the percentage entry and time spent in open arms in the elevated plus maze. Summing up, it is observed that OND exhibits antidepressant-like effects, possibly mediated through postsynaptic 5-HT3 receptors.