Commercial bacterins for Glässer's disease are widely used for the prevention of this disease caused by Haemophilus parasuis; however, the protective efficacy varies depending on the strain and serovar. Bacterial ghosts (BGs) are empty bacterial envelopes that, unlike classic bacterins, suffer no denaturing steps during their production. These properties may lead to superior protection. In this study, a BG vaccine generated from the Haemophilus parasuis serovar 5 reference strain Nagasaki was prepared and used to inoculate piglets. The efficacy of the BG vaccine was evaluated by clinical, bacteriological, serological, and postmortem examinations. Inactivated bacterin (IB) and a placebo control (PC) were compared with the BG vaccine in this study. The results showed that the piglets inoculated with the BG vaccine developed higher antibody activity and higher gamma interferon and interleukin 4 levels than those vaccinated with IB or those in the PC group after primary and secondary exposure to the antigens and challenge. CD4(+) T lymphocyte levels were observed to increase following secondary immunization more in the BG-vaccinated group than in the IB (P < 0.05) and PC (P < 0.05) groups. CD8(+) T lymphocyte levels increased dramatically in all three groups after challenge, and the differences between groups were all significant (P < 0.05). There were fewer tissue lesions and lower bacterial loads in the tissue homogenates in the BG group after challenge. The results suggest that higher CD4(+) T lymphocyte levels and both CD4(+) major histocompatibility complex class II-restricted Th1-type and Th2-type immune responses in the BG group are relevant for protection.