Background and Objectives: Depression is one of the most common psychiatric disorders, which can be detected and continued through stressful life events. Since the medical treatment of depression, is longterm use of antidepressants, therefore, this research was performed to compare the effects of fluoxetine and imipramine on depression. Methods:In this experimental study, 24 male Wistar rats (age range, 180±20gr), were used. Animals were divided into four groups of 6 each, including: Control, under immobilization stress, fluoxetinetreated (dose, 20mg/kg), and the Imipramine-treated (dose, 30mg/kg). Induction of immobilization stress was conducted by limiting polyethylene for 14 days. At the end of the treatment period, the antidepressant effects of the drugs in the treatment groups, were evaluated using tail suspension test. Then, serum levels of corticosterone and glucose, were measured. Results:In this study, the immobility time in the patient group significantly increased as compared to the control group. However, administration of fluoxetine and imipramine decreased immobility time compared to the patient group. Also, immobilization stress significantly decreased corticosterone and serum glucose compared to the control group. While, administration of fluoxetine increased corticosterone levels compared to the patient group, but administration of imipramine induced no change. Administration of fluoxetine or imipramine also increased glucose levels compared to the patient group. Conclusion:The results showed that immobilization stress causes depression-like behavior, and fluoxetine compared to imipramine has more improving effects in the reduction of depression-like behavior.