This study intends to explore the health and immunologly mechanism of fermented soybean meal replacing fish meal affecting the growth of the Litopenaeus vannamei based on varying immune-related enzymes activity and genes transcription levels. Five experiment diets were designed, in which 30% of fish meal diet (FM) as the control group, and 4% (FSM4), 8% (FSM8), 12% (FSM12) and 16% (FSM16) of the fermented soybean meal were used to replace 9.7%, 19.4%, 29.1% and 38.8% of the fish meal respectively. After 60-day feeding test for L. vannamei[initial weight=(7.62±0.23) g], the growth performance, muscle nutrition composition, serum and hepatopancreas immune enzymes activity, the expression levels of HSP70 mRNA in hepatopancreas and Toll receptor mRNA, IMD mRNA and LZM mRNA in gill were determined. The results indicated that the substitution of fermented soybean meal for fish meal had no significant effect on the survival rate of the shrimp compared with the control group, both too low and too high levels of fermented soybean meal reduced the specific growth rate of shrimp. Muscle crude protein content was lower in the addition group of fermented soybean meal than the FM group with no significant difference except FSM12, crude fat has a tendency to decrease with the increase of fermented soybean meal, and the lowest value was found in the FSM16 group. The serum alanine aminotransferase (ALT) in FSM4 and FSM16 groups was significantly higher than that of control group, and the aspartate amino transferase (AST) was the highest and lowest in FSM4 group and FSM8 group respectively; except FSM12 group, serum ALP showed no marked difference between other FSM groups and the control group; as for TP in serum and MDA in hepatopancreas, there was no statistic difference either between FSM groups (except FSM16 group) and the control. With the increase of the amount of fermented soybean meal, the level of gill Toll receptor mRNA expression increased, and the level of IMD mRNA expression increased first and then decreased, and excessive or less of the added fermented soybean meal would decrease the expression of LZM mRNA in gill, while the expression of HSP70 mRNA in hepatopancreas increased with the increase of fermented soybean meal. To sum up, in the conditions of this experiment, optimum amount of the fermented soybean meal was 8% to 12%, i.e replacing 19.4% –29.1% of fish meal without affecting the growth of the tested shrimp, accompanied by improved immune-enzyme activity and changed expression of immune related genes, however, too high substitution can cause excessive stress response.