Epidemiological studies demonstrate that affective disorders are at least twice as common in women as in men, but surprisingly, very few preclinical studies have been conducted on female experimental animals. Therefore, the necessity of developing valid animal models for studying the pathophysiology of stress-related disorders in women is obvious. Chronic social stress has the potential to induce depression in humans and therefore we characterize here a chronic social instability stress paradigm in female rats. This consists of a 4-week period with alternating stressful social situations, including phases of isolation and crowding, in an unpredictable manner. At the physiological level, increased adrenal weight and plasma corticosterone levels indicated hyperactivity of the hypothalamus-pituitary-adrenal axis. Elevated plasma luteinizing hormone and disruption of the estrus cycle together with increased serum prolactin levels revealed disrupted regulation of the hypothalamus-pituitary-gonadal axis. Body temperature regulation was affected during the last week of stress such that stressed rats reduced their body temperature less during the rest phase than the controls, thus exhibiting a flattened temperature curve. Behaviorally, chronically stressed rats showed reduced sucrose preference and food intake. However, we did not observe any effect of stress on performance in the forced swim test and hippocampal neurotrophin levels were similarly unaffected. Our results indicate that, by using this social instability paradigm, female rats can be kept under chronic stress for weeks without habituation, and that ultimately the animals develop a depressive-like phenotype. This model may provide a valuable tool for further analyses of the neurobiology of stress-related disorders in women and has the potential to serve as a paradigm for screening novel antidepressant drugs with special efficacy in women.