The present study was undertaken to investigate whether chronic agomelatine treatment which acts as an agonist of melatonergic MT1 and MT2 receptors would block unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice as compared with fluoxetine and melatonin. Male inbred BALB/c mice were treated with agomelatine (10 mg/kg i.p.), melatonin (10 mg/kg ip), fluoxetine (15 mg/kg ip), or vehicle for 5 weeks. All compounds tested blocked the stress-induced deficit in coat state during the UCMS procedure, increased total latency of grooming in the splash test, decreased attack frequency in the resident/intruder test, and reduced immobility time in the tail suspension and forced swimming tests. All compounds also reduced the levels of plasma adrenocorticotropic hormone, interleukin 6, and tumor necrosis factor-alpha in stressed mice. The results of this study indicate that agomelatine, which has a novel mode of action, can be as effective as fluoxetine for the treatment of depression.