Background: Acne vulgaris afficts, more than fifty million people in the United State and the severity of this disorder is associated with the immune responsexto Propionibacterium acnes (P. acnes). Systemic therapies for acne target P. acnes using antibiotics, or target the follicle with retinoids such as isotretinoin. The latter systemic treatment is highly effective but also carries a risk of side effects including immune imbalance, hyperlipidemia, and teratogenicity. Despite substantial research into potential new therapies for this common disease, vaccines against acne vulgaris are not yet available. Methods and Findings: Here we create an acne vaccine targeting a cell wall-anchored sialidase of P. acnes. The importance of sialidase to disease pathogenesis is shown by treatment of a human sebocyte cell line with recombinant sialidase that increased susceptibility to P-acnes cytotoxicity and adhesion. Mice immunized with sialidase elicit a detectable antibody, the anti-sialidase serum effectively neutralized the cytotoxicity of P. acnes in vitro, and P. acnes-induced interleukin-8 (IL-8) production in human sebocytes. Furthermore, the sialidase-immunized mice provided protective immunity against P. acnes in vivo as this treatment blocked an increase in ear thickness and release of pro-inflammatory macrophage inflammatory protein (MIP-2) cytokine. Conclusions: Results indicated that acne vaccines open novel therapeutic avenues for acne vulgaris and other P. acnes associated diseases.