To evaluate the immune effect of an oral vaccine of Edwardsiella ictaluri on channel catfish, E. ictaluri were killed by formalin and sodium alginate was used to prepare the oral microsphere vaccine. The experimental animals were randomly divided into four groups, including E. ictaluri oral microspheres vaccine group, formalin inactivated vaccine group, microspheres without antigen group and control group. After oral immunization, the effect of the vaccine was evaluated by serum non-specific immune parameters, antibody titers and relative percent survival detection. Results showed the serum lysozyme activity, total superoxide disumutase (T-SOD) activity and alternative pathway complement (ACH50) activity significantly increased in vaccinated channel catfish, showing the influence of the relativity gene transcription of the Ictucurus punctatus induced by these oral vaccines respectively by real-time PCR. The results showed that the I. punctatus fed the E. ictaluri oral microsphere vaccine can acquire longer time of nonspecific imumunity. The serum agglutination titers peaked to 1:16 at 5th week. The specific antibodies could still be detected at 7th week. The relative percent survival of channel catfish was 60.7%, far higher than formalin inactivated vaccine group (14.3%) and microspheres without antigen group (10.7%). From the results of real-time PCR, it is found that in the E. ictaluri oral microspheres vaccine group, the expression of immunity genes increased more notably than other groups during the 48 hours after injection, especially in the kidney and spleen. In conclusion, the oral microspheres vaccine of E. ictaluri was able to enhance the non-specific immune function and effective for preventing E. ictaluri disease.