Haemophilus parasuis is thought to be part of the normal nasal microbiota but it is also the etiological agent of Glässer’s disease, a systemic disease that causes large economical losses, especially in nursery piglets. Strains of H. parasuis display a wide range of degree of virulence. The role of this bacterium in respiratory disease is not clear, but it has been found in the lung as a previous step to systemic invasion. Virulent strains have been shown to resist phagocytosis by porcine alveolar macrophages (PAMs) in vitro and have been detected in the lung after intranasal inoculation of piglets. On the other hand, non-virulent nasal strains are cleared from the lower respiratory tract, probably due to the action of the macrophages. In fact, virulent strains delay activation of PAMs, and survive in the lung for subsequent systemic spread and induction of the strong inflammation characteristic of Glässer’s disease. Genomic comparison of H. parasuis strains from different clinical origins demonstrated a family of genes differentially present depending on the virulence potential of the strains. These genes were termed virulence-associated trimeric autotransporters (vtaA). Analysis of the sequence of these genes has allowed the design of a PCR test for the discrimination of potentially virulent strains. Additional data supporting the role of some VtaA in virulence has been also reported, and VtaA8 and 9 were shown to play a role in phagocytosis resistance. Monoclonal antibody (mAb) 69C6, produced against VtaA8, reacted with the surface of virulent strains and was effective in opsonizing a resistant H. parasuis strain to render it susceptible to phagocytosis. MAb 69C6 has allowed the identification of an epitope in the C terminus of the passenger domain of the VtaAs associated to virulent strains. Induction of antibodies against the 69C6 epitope by vaccination would allow specific targeting virulent H. parasuis strains.