The anti-serotonergic effects of parthenolide (PTL) demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, PTL (0.5-2 mg kg-1) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg-1) that induced depressant-like effects were found to significantly reduce 5-hydroxytryptophan-induced head twitch response. Interaction studies revealed that the depressant-like effects of PTL (1 mg kg-1) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of PTL (1 and 2 mg kg-1) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of PTL (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.