Abstract: The immunological efficacy of Streptococcus agalactiae surface immunogenic protein (SIP) oral vaccine on tilapia (Oreochromis niloticus) was studied. Randomly grouped fish were injected with the inactivated vaccine as the positive control (Group Inactivated Vaccine), or orally administered with SIP vaccine (Group SIP Vaccine) for treatment or PBS as the negative control (Group Negative Control). Spleen samples from the tilapias were collected at 0, 7, 14 and 28 d after the immunization. The gene expressions of the cluster determinant 4 (CD4), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor α(TNF-α) and nuclear transcription factors κB(NF-κB) were determined by the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Four weeks after the treatments, the groups were challenged by the artificial infection of S. agalactiae to observe the relative percent survivals (RPS) on the fish. The results show that the expressions on CD4, IL-8, IL-10, TNF-α and NF-κB genes of Group SIP Vaccine and Group Inactivated Vaccine increased in varying degrees, and were significantly higher (P < 0.05) than those of Group Negative Control. The death rates of fish in Group SIP Vaccine and Group Inactivated Vaccine were significantly lower (P < 0.05) than that of Group Negative Control. The RPS of Group Inactivated Vaccine was higher than that of Group SIP Vaccine, but not significantly different (P>0.05). It appeared that the SIP oral vaccine could be used with satisfaction in protecting tilapias from S. agalactiae infection.