The yeast particulate zymosan (Zy) activates innate immune system cells and induces cytokine secretion. There is also evidence that Zy can affect biologic responses to bacterial lipopolysaccharide (LPS) and that the pathways by which these two agents act upon immune cells are only partially distinct. The present experiments assessed the ability of Zy to elicit CNS-mediated sickness symptoms and to alter their responses to LPS. In Experiment 1, Zy induced elements of the sickness behavior syndrome dose-responsively in Long-Evans rats, as indicated by reductions in consumption of a highly palatable bait and in body temperature. In Experiment 2, Zy exerted a priming effect, sensitizing animals to subsequent LPS as measured by reductions in bait consumption, 24-h laboratory chow intake, and body temperature. Experiment 3 failed to provide evidence for LPS-to-Zy cross-tolerance but did indicate that the administration of Zy disrupts previously acquired LPS tolerance. These results suggest that the specifics of exposure to microbially derived innate immune activators have to be taken into account in investigating the biologic bases of sickness behaviors and developing models of coinfection.