Abstract: Bacteria ghosts is a new type vaccine, which can induce strong cellular immunity, humoral immunity and mucosal immunity. This study explored the immune efficacy of Edwardsiella bacteria ghosts (ETG) and Formalin killed cell (FKC) vaccinated Oreochromis niloticus by intraperitoneal injection and oral routes. Serum at 14, 21, 28 day post-vaccination were collected to analyze specific IgM antibody, acid phosphatase (ACP), superoxide dismutase (SOD), and head kidney and spleen were used to measure the expression of IL-1, TNF, IFN, Caspase3, and immunologic potency (relative percent survival, RPS) was calculated. Our results indicated that vaccine groups had significantly increased (P<0.01) specific antibody levels compared with control at 28 days post-secondary vaccination, and ETG intraperitoneal injection group had significantly higher antibody levels (P<0.01) than FKC oral group. Superoxide enzyme (SOD) activity and acid phosphatase (ACP) of vaccinated groups were significantly higher (P<0.05) than those of the control groups (Group E and F), and the vaccine trials group (Group A and B) and TNF, IL-1 and IFN were significantly higher (P<0.05) than those of the control (Group E and F) at 28 day post-vaccination. The relative protective survival (RPS) of all vaccine groups was significantly higher (P<0.05) than that of the control groups. RPS of ETG injection and ETG oral were 79% and 77%, respectively, and RPS of FKC injection and FKC oral were 62% and 60%, respectively. However, they were no significant difference between ETG and FKC. These results suggest that bacteria ghost is good candidate in preventing Edwardsiella tarda disease in Oreochromis niloticus with great research value and application prospects.