Chronic stress is widely regarded as a key risk factor for a variety of diseases. A large number of paradigms have been used to induce chronic stress in rodents. However, many of these paradigms do not consider the etiology of human stress-associated disorders, where the stressors involved are mostly of social nature and the effects of the stress exposure persist even if the stressor is discontinued. In addition, many chronic stress paradigms are problematic with regard to stress adaptation, continuity, duration and applicability. Here we describe and validate a novel chronic social stress paradigm in male mice during adolescence. We demonstrate persistent effects of chronic social stress after 1 week of rest, including altered adrenal sensitivity, decreased expression of corticosteroid receptors in the hippocampus and increased anxiety. In addition, pharmacological treatments with the antidepressant paroxetine (SSRI) or with the corticotropin-releasing hormone receptor 1 antagonist DMP696 were able to prevent aversive long-term consequences of chronic social stress. In conclusion, this novel chronic stress paradigm results in persistent alterations of hypothalamus-pituitary-adrenal axis function and behavior, which are reversible by pharmacological treatment. Moreover, this paradigm allows to investigate the interaction of genetic susceptibility and environmental risk factors.