Actinobacillus pleuropneumoniae is the major etiological agent of swine pleuropneumonia that causes critical economic losses in swine industry. The use of DNA vaccines encoding Apx exotoxin structural proteins is a promising novel approach for immunization against A. pleuropneumoniae. The goal of this study was to design DNA vaccines which encode the gene of ApxIA or ApxIIA, and to evaluate the elicited immune responses and protective efficacy in mice. Significant humoral immune responses were induced by these DNA vaccines through intramuscular immunization. The IgG subclass (IgG1 and IgG2a) analysis indicates that divalent DNA vaccine induces both Th1 and Th2 immune responses. The protective efficacy was evaluated by the survival against lethal challenge with A. pleuropneumoniae serotype 1. The groups of vaccination with pcDNA-apxIA or divalent (pcDNA-apxIA and pcDNA-apxIIA) DNA vaccine provided protective efficacy significantly higher than that of the negative control groups (P<0.05). However, pcDNA-apxIIA vaccine conferred protection was limited and not significant than that of the negative control groups (P>0.05). These results show that the divalent DNA vaccine could confer the best protection. This finding indicates that DNA immunization should facilitate the development of a 'third-generation' of vaccines and provide a novel strategy against A. pleuropneumoniae infection.