Background: Depression is a common psychiatric illness but conventional antidepressants are often shows unpredictable response. Pharmacological profiles of many atypical antipsychotics have potential antidepressant effect. Ziprasidone is an atypical antidepressant with 5HT1A agonistic activity and 5HT1D, 5HT2A and D2 receptors antagonistic activity. It’s a potential candidate for evaluating possible antidepressant activity.Methods: Behavioural despair test are widely used for evaluation of potential antidepressant molecule. Tail suspension test is a variant of behavioural despair test. Healthy male Wistar albino rat 18 in number and weighing between of 150-200 grams were divided in 3 groups with 6 rats in each group. Group A was treated with 0.9% Normal Saline, Group B with Fluoxetine and Group C with Ziprasidone for 28 days. Tail suspension test was done on day 0, 7, 14, 21 and 28 days.Results: In comparison to Normal saline both the drugs shows significant antidepressant activity after 28 days of treatment. While antidepressant activity of fluoxetine started to appear from day 7; that of ziprasidone started to appear from 14th day.Conclusions: Ziprasidone can be suitable candidate for clinical trials of Major Depressive Disorders not responding to conventional antidepressant.