ABSTRACTPorcine contagious pleuropneumonia, caused byActinobacillus pleuropneumoniae, has a major impact on economics, ecology, and animal welfare in the pig-rearing industry.Propionibacterium acnes, a facultative anaerobic Gram-positive corynebacterium, exists widely in normal healthy adult animals. We have shown previously thatP. acnescan preventA. pleuropneumoniaeinfections in mice and pigs. To elucidate the mechanism of this effect and to identify novelA. pleuropneumoniaevaccines, the role of anti-P. acnesantibodies in preventing infection was analyzed by indirect immunofluorescence and opsonophagocytosis assaysin vitro. The role of the specific humoral immune response induced byP. acneswas confirmed in a B cell depletion mouse model. The survival rates of mice challenged withA. pleuropneumoniaeexhibited a highly significant positive rank correlation with the levels of anti-P. acnesantibodies. The specific antibodies induced byP. acneshad the ability to combine withA. pleuropneumoniaeand increase opsonization ofA. pleuropneumoniaefor phagocytosis. Furthermore, analysis in the murine B cell depletion model confirmed that the humoral immune response induced byP. acnesplayed an important role in resistance toA. pleuropneumoniaeinfection. In this study, we further elucidated the reasons thatP. acnescan preventA. pleuropneumoniaeinfection, which provides useful evidence for the development of heterologous vaccines for the control of porcine contagious pleuropneumonia.