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The purpose of this study was to optimize the medium components for high productivity of Haemophilus parasuis serovar 5 through statistical approach. Plakett-Burman experimental design was initially applied to identify the factors that influenced the biomass of H. parasuis. Based on the response surface and canonical analyses, the optimum concentrations of the critical components were obtained as follows: 43·55 g l−1, yeast extract; 1·05 g l−1, sodium chloride; 11·63% (v/v), phosphate buffer; 10% (v/v), bovine serum; and 20 μg l−1, nicotinamide adenine dinucleotide. The number of viable cells of H. parasuis reached 4·7*109 CFU ml−1 and the productivity was 4·7*109 CFU ml−1 h−1 after cultivation in the optimal medium in 3 l fermentor, increasing 2·5 times and 3·9 times more than that in tryptone soy broth medium, respectively.Significance and Impact of the Study: This study is the first report on statistical optimization of medium components for the fermentation of Haemophilus parasuis serovar 5. The improved medium was highly efficient, less expensive (its cost was $1·16 l−1, while that of tryptone soy broth was $4·00 l−1) and has been used for large-scale production in Wuhan Keqian Animal Biology Product Co. Ltd, China, and it will improve the industrialization of H. parasuis worldwide.