Vibriosis is a severe infection occurring in many commercially important marine fish species. In this study， vaccines containing Vibrio harveyi recombinant outer membrane protein K (rOmpK)， outer membrane protein U (rOmpU) and rOmpK-OmpU fusion protein in addition to the metabolizable Montanide ISA 763 A VG adjuvant were developed and evaluated in the orange-spotted grouper. The results indicate that recombinant V. harveyi protein-based vaccines resulted in a remarkably higher expression of IL-1β and IL-8 at 24 hr， and greater antibody production， as early as 2 weeks postimmunization. Notably， enhanced immune responses and significant protective efficacy against V. harveyi infections were observed in the fusion protein vaccine-injected fishes with relative per cent survival value of 81.8%. Additionally， the rOmpK-OmpU antisera presented a high bactericidal effect on not only V. harveyi， but also Vibrio parahaermolyticus and Vibrio alginolyticus. Our results demonstrated that the fusion protein rOmpK-OmpU was an effective vaccine candidate that exhibited potentially great versatility for controlling vibrio infections.