Abstract: The aim of this paper was to identify a tilapia strain that is the most resistant to the infection of Streptococcus agalactiae. The serum biochemical parameters and histopathology of Blue tilapia (Oreochromis aureus) " Xia’ao No.1”, Nile tilapia (Oreochromis niloticus) " 99 strain”, GIFT tilapia (Oreochromis niloticus♀×Oreochromis niloticus♂) " Zhongwei No.1”, Hybrid tilapia (Oreochromis niloticus♀×Oreochromis aureus♂) infected by S. agalactiae were investigated. They were cultured on (33±1) ℃. All fish were acclimated to the laboratory conditions for one week then artificially inducedS. agalactiae to the fish. The cumulative mortality was recorded at different time points. Blood and tissue samples were collected at 0, 12h, 24h, 48h and 72h after infection. The result showed that the cumulative mortality of Hybrid tilapia was significantly lower than that of other species; Glutamic-oxaloacetic transamnase (AST) activity of Hybrid tilapia was consistently lower than that of other three strains (P<0.05); compared with initial measurement, globulin of Nile tilapia and Hybrid tilapia increased by 1.13 times and 1.41 times respectively at 72h after infection. Albumin/globulin (A/G) index of Hybrid tilapia showed no significantly difference (P>0.05), while that of other three species was significantly lower after infection (P<0.05); Alkaline phosphatase (AKP) activity of Nile tilapia decreased significantly at 72h after infection (P<0.05) while AKP levels of Blue tilapia and GIFT tilapia increased first followed by decrease, and AKP of Hybrid tilapia showed no significantly difference (P＞0.05). Lactic dehydrogenase (LDH) of all four strains increased significantly on the progress of disease after infection (P<0.05). Superoxide dismutase (SOD) activities of Blue tilapia, GIFT tilapia and Hybrid tilapia increased significantly at 48h after infection (P<0.05). Lysozyme (LZM) activities of Hybrid tilapia were consistently higher than that of other three strains (P<0.05). Hepatocytes of GIFT and Hybrid tilapia showed hydropic degeneration, while hepatocytes of Blue tilapia, Nile tilapia showed highly vacuolation and macrovesicular steatosis. The spleen of all challenged strains showed had serious splenitis while the spleen of Blue tilapia, Nile tilapia and GIFT tilapia contained a large number of hemosiderin deposition. Renal glomerular atrophy, degeneration and necrosis in renal tubule epithelial cell were apparent after infection. The results indicated that Hybrid tilapia was the most resistant toS. agalactiae; AST in serum was correlated positively with liver damage; LZM level was correlated positively with the anti-Streptococcus ability.