Stressor and cytokine challenges provoke several common effects, and may synergistically influence behavioral and neurochemical functioning. In the present investigation, we assessed whether the effects of poly I:C would be influenced when administered on a backdrop of a psychosocial stressor. In naïve mice, poly I:C (2mg/kg) modestly increased sickness behaviors, plasma IL-6, TNF-alpha and IL-10 levels, but did not affect IL-1, IL-4, or IFN-gamma. The viral analogue also increased plasma corticosterone levels and norepinephrine (NE) utilization within the paraventricular hypothalamus (PVN) and hippocampus. However, among mice that had experienced social disruption (comprising 14 days of isolation followed by regrouping), the behavioral, IL-6, IL-10, and corticoid alterations provoked by poly I:C were markedly augmented. Moreover, following social disruption the effect of poly I:C on NE utilization was increased within the PVN, prefrontal cortex and central amygdala, as was serotonin utilization within the hippocampus. The effects of poly I:C were likewise augmented following social disruption engendered by introducing mice to strangers.. However, among mice that had previously been exposed to a chronic, variable psychosocial stressor regimen, the augmented behavioral, neuroendocrine and monoamine effects of poly I:C were absent, and IL-6 and IL-10 levels were reduced relative to mice that had not been chronically stressed. In contrast, levels of IL-1 beta and IFN-gamma were increased. Mechanisms that might be responsible for the interactive effects of social disruption and immune activation are presented, and the data were related to depressive symptoms associated with stressor and cytokine treatments.