Rodents utilize chemical cues to recognize and avoid other conspecifics infected with pathogens. These cues are recognized by healthy conspecifics via the vomeronasal or accessory olfactory system, triggering an innate form of avoidance behavior. However, the molecular identity of the sensory neurons and the higher neural circuits involved in the detection of sick conspecifics remain poorly understood. We employed mice that are in an acute state of inflammation induced by systemic administration of lipopolysaccharide (LPS). Through conditional knockout of the G-protein Gαi2 and deletion of other key sensory transduction molecules (Trpc2 and a cluster of 16 vomeronasal type 1 receptors), in combination with behavioral testing, subcellular Ca2+ imaging, and pS6 and c-Fos neuronal activity mapping in freely behaving mice, we show that the Gαi2+ vomeronasal subsystem is required for the detection and avoidance of LPS-treated mice. The active components underlying this avoidance are contained in urine whereas feces extract and two selected bile acids, although detected in a Gαi2-dependent manner, failed to evoke avoidance behavior. Our analyses of dendritic Ca2+responses in vomeronasal sensory neurons provide insight into the Gαi2-dependent discrimination capabilities of these neurons for urine fractions from LPS-treated mice. We observed Gαi2-dependent stimulation of medial amygdala, ventromedial hypothalamus, periaqueductal grey, as well as the lateral habenula, a previously unknown target involved in these tasks. Thus, these results indicate that the sensing and avoidance of LPS-treated sick conspecifics depends on the Gαi2 vomeronasal subsystem, and on brain circuits downstream of the olfactory periphery and in the lateral habenula. These results provide new insights into the neural substrates and circuit logic of the sensing of inflammation in mice.