ABSTRACT Relapse is highly prevalent after detoxification and depression. Due to the advantages of venlafaxine compared with other antidepressants, it is expected that venlafaxine administration may reduce relapse after detoxification and depression. This study aimed to evaluate the effects of venlafaxine on depression-induced relapse to morphine dependence after methadone detoxification. Eighty Sprague-Dawley rats were habituated and conditioned with morphine (10 mg/kg, S.C., for 4 days). After that, primary forced swimming and conditioned place preference (CPP) were tested. They were followed by methadone (70 mg/kg/day, P.O., for 7 days) administration, extinguishing, forced swimming stress (FSS) and administration of venlafaxine (80 mg/kg/day, I.P., for 7 days). Finally same tests were performed. Administration of venlafaxine resulted in a decrement in final preference scores associated with a prime morphine injection (PMI) compared to the primary scores in methadone treated (MTD+) animals. In a swimming test, venlafaxine increased the amount of final floating and decreased final activity scores compared with the primary scores after administration of methadone. Venlafaxine reduced locomotor activity in MTD+ animals in the final test with PMI. There was a positive correlation between the final activity and preference scores after PMI. In conclusion, venlafaxine improved anxiety and depression-induced relapse on methadone detoxified rats.