Pseudorabies virus (PRV) is an alphaherpesvirus that infects the peripheral nervous system (PNS). The natural host of PRV is the swine, but it can infect most mammals, including cattle, rodents and dogs. In these non-natural hosts, PRV always causes a severe acute and lethal neuropathy called the "mad itch", which is uncommon in swine. So far, the pathophysiological and immunological processes leading to the development of the neuropathic itch, and death of the animal are unclear.Using a footpad inoculation model, we established that mice inoculated with PRV-Becker (virulent strain) develop a severe pruritus in the foot and become moribund at 82 hours post-inoculation (hpi). We found necrosis and inflammation with a massive neutrophil infiltration only in the footpad and DRGs by H&E staining. PRV load was detected in the foot, PNS and CNS tissues by quantitative-RT-PCR. Infected mice had elevated plasma levels of pro-inflammatory cytokines (IL6 and G-CSF) and chemokines (Gro-1 and MCP-1). Significant IL6 and G-CSF levels were detected in several tissues at 82hpi. High plasma levels of C-reactive protein confirmed the acute inflammatory response to PRV-Becker infection. Moreover, mice inoculated with PRV-Bartha (attenuated, live vaccine strain), did not develop pruritus at 82hpi. PRV-Bartha also replicated in the PNS, infection spread further in the brain than PRV-Becker. PRV-Bartha infection did not induce the specific and lethal systemic inflammatory response seen with PRV-Becker. Overall, we demonstrated the importance of inflammation in the clinical outcome of PRV infection in mice and provide new insights into the process of PRV-induced neuroinflammation.Pseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens such as herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV). The natural host of PRV is the swine but it can infect most mammals. In susceptible animals other than pigs, PRV infection always causes a characteristic lethal pruritus known as the "mad itch". The role of the immune response in the clinical outcome of PRV infection is still poorly understood. Here, we show that a systemic host inflammatory response is responsible for the severe pruritus and acute death of mice infected with virulent PRV-Becker but not attenuated strain PRV-Bartha. In addition, we identified IL-6 and G-CSF as two main cytokines that play crucial roles in the regulation of this process. Our findings give new insights into neuroinflammatory diseases and strengthen further the similarities between VZV and PRV infections at the level of innate immunity.