Preclinical Research 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.