Objective To study the antidepressant effect of a polypeptide drugs—XMT. Methods Using the suspension test, forced swim test, 5-hydroxy-L-tryptophan (5-HTP) induced head twitch response test and yohimbine induced lethality test in mice, the antidepressant effect and the possible mechanisms of XMT were measured. Results In the tail suspension test, repeated administration (0.3-10 mg/kg, sc) with XMT for 5 d reduced the immobility time in mice (P<0.05 vs the normal saline control). XMT (0.3-5.0 mg/kg, sc for 5 d) can reduced the immobility time in the forced swim test in mice (P<0.05 vs the normal saline control), while there was no central stimulated effect during the effective doses (0.3-5.0 mg/kg). Furthermore, XMT in repeated doses (5.0 and 1.0 mg/kg, sc for 5 d) decreased the 5-HTP induced head twitch response in mice (P<0.01, P<0.05 vs the normal saline control), while it had no effect on the yohimbine toxicity (P>0.05 vs the normal saline control). Conclusion XMT has antidepressant effect which may be related to the property of inhibition the 5-HT2 receptor, etc.