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One of the highest priority areas for improvement is the development of effective strategies for decreasing disease mortality levels in aquaculture production, a better understanding of the components of the fish immune system and their functions in the context of pathogen invasion is needed. Tilapia is the most common fish in South China, and Streptococcus agalactiae has become the most serious disease problem for tilapia industry in China. Here, we profiled gene expression differences between tilapia differing in their susceptibility to S. agalactiae both basally (before infection) and at three early timepoints post-infection (5 h, 50 h, and 7 d). Between group comparisons revealed 5756 unique genes differentially expressed greater than 2-fold at one or more timepoints. And the resistant fish showed much more strong ability in pathogen recognition, antigen presentation, immune activation, while the susceptible fish showed fast activation of apoptosis. Taken together, the immune profiles expand our knowledge for molecular mechanisms for disease resistance, as well as provide solid molecular resources for further identification of the candidate markers for disease-resistant selection and evaluation of disease prevention and treatment options for tilapia industry.Gene expression differences between tilapia with different susceptibility to S. agalactiae were profiled.Between group comparison revealed 5,756 unique genes differentially expressed at one or more timepoints.The resistant fish showed strong ability in pathogen recognition, antigen presentation, immune activation.