Although cytokine-induced sickness behavior is now well-established, the mechanisms by which chronic inflammation and depression are linked still remain elusive. Therefore this study aimed to develop a suitable model to identify the neurobiological basis of depressive-like behavior induced by chronic inflammation, independently of sickness behavior. We chose to measure the behavioral consequences of chronic inoculation of mice with Bacillus Calmette-Guerin (BCG), which has been shown to chronically activate both lung and brain indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates the occurrence of depressive-like behavior following acute innate immune system activation. BCG inoculation induced an acute episode of sickness (approximately 5 days) that was followed by development of delayed depressive-like behaviors lasting over several weeks. Transient body weight loss, reduction of motor activity and the febrile response to BCG were dissociated temporarily from a sustained increase in the duration of immobility in both forced swim and tail suspension tests, reduced voluntary wheel running and decreased preference for sucrose (a test of anhedonia). Moreover, we show that a distinct pattern of cytokine production and IDO activation parallels the transition from sickness to depression. Protracted depressive-like behavior, but not sickness behavior, was associated with sustained increase in plasma interferon-gamma and TNF-alpha concentrations and peripheral IDO activation. Together, these promising new data establish BCG inoculation of mice as a reliable rodent model of chronic inflammation-induced depressive-like behaviors that recapitulate many clinical observations and provide important clues about the neurobiological basis through which cytokines may have an impact on affective behaviors.