Recently, a skin ulcerative disease caused by Vibrio mimicus has led to heavy economic losses in catfish, including yellow catfish, southern catfish, and Zhengchuan catfish in China. Currently, there was no effective method of controlling the outbreak of this disease. In this study, the bacterial isolates were obtained from dying channel catfish and identified as V. mimicus, which consist of formalininactivated V. mimicus (antigen). After first immunization, four weeks later, fishes were exposed to V. mimicus and the immune response was analyzed: Fish survival, respiratory burst activity of blood leukocytes, serum agglutination titers, and lysozyme activity, every week (during four weeks). Survival was up 90%. Respiratory burst activity of blood leukocytes, serum agglutination titers, and lysozyme activity were determined at 1, 2, 3, and 4 weeks after primary immunization. Immunization of channel catfish protected hosts against V. mimicus infection with a survival percentage of more than 90%. Respiratory burst activity of blood leukocytes was not affected by vaccination. Serum agglutination titer and lysozyme activity were significantly increased after immunization, in comparison with unvaccinated control fish. The obtained results indicated that vaccination is an effective method to control the outbreaks of V. mimicus through regulation of the humoral immune response.