Inflammatory acne vulgaris afflicts hundreds of millions of people globally. Propionibacterium acnes, an opportunistic skin bacterium, has been linked to the pathogenesis of acne vulgaris. Our results show that a secretory Christie-Atkins-Munch-Petersen (CAMP) factor of P.áacnes is up-regulated in anaerobic cultures. Mutation of CAMP factor significantly diminishes P.áacnes colonization and inflammation in mice, demonstrating the essential role of CAMP factor in the cytotoxicity of P.áacnes. Vaccination of mice with CAMP factor considerably reduced the growth of P.áacnes and production of MIP-2, a murine counterpart of human IL-8. Acne lesions were collected from patients to establish an exávivo acne model for validation of the efficacy of CAMP factor antibodies in the neutralization of the acne inflammatory response. The P.áacnes CAMP factor and two proinflammatory cytokines (IL-8 and IL-1β) were expressed at higher levels in acne lesions than those in nonlesional skin. Incubation of exávivo acne explants with monoclonal antibodies to CAMP factor markedly attenuated the amounts of IL-8 and IL-1β. Our work using an exávivo acne model shows that P.áacnes CAMP factor is an essential source of inflammation in acne vulgaris.