Actinobacillus pleuropneumoniae (App) and Mycoplasma hyopneumoniae (Mhp) cause porcine pleuropneumonia and mycoplasmal pneumonia, respectively, and have serious impacts on the swine industry because they retard the growth of pigs. To protect pigs against these diseases, we have developed a multivalent vaccine consisting of App bacterins, APP RTX toxins (Apx toxins), and Mhp bacterin and adhesin protein. This vaccine induced the production of higher levels of antibodies against App and Mhp than the commercial vaccine (Nisseiken Swine APM Inactivated Vaccine). Furthermore, the vaccine efficiently protected pigs against virulent App challenge, showing promise as an efficient vaccine for the prevention of two important respiratory diseases, porcine pleuropneumonia and mycoplasmal pneumonia.