Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor (TNF) interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury.