The suprachiasmatic nucleus (SCN) is involved in regulating many biological rhythms. Several lines of research implicate the SCN in affective behavior. The SCN is directly involved in regulating the daily rhythms of the hypothalamo-pituitary-adrenal (HPA) axis hormones involved in stress. Bilateral lesions of the SCN disrupt both the rhythms and the basal levels of the HPA axis hormones involved in coping with stress. Moreover, stress can affect the biological rhythms regulated by the SCN, and disruption of biological rhythms in turn can cause stress. The present study assessed the effect of bilateral destruction of the SCN on behavioral despair, an animal model of depression sensitive to antidepressant treatment. The results indicate that bilateral destruction of the SCN results in reduced immobility in the second forced swimming test (FST) compared to sham controls and animals with incomplete lesions. These results indicate that bilateral destruction of the SCN has a protective effect in the induction of behavioral despair which may arise out of disruption of the secretion of the HPA axis hormones and/or of the neural connections between the SCN and the limbic structures that modulate the response to swim stress.