Foaming reduces the working volume and limits the biosynthesis of macrolide immunosuppressant ascomycin (FK520) in the batch fermentation process of Streptomyces hygroscopicus FS-35 in a 7.5 L bioreactor. To find the relation between FK520 production and foaming, effects of 10 fermentation parameters including organic acids and membrane permeability were investigated. The results suggest that acetate accumulation caused by short period oxygen deficiency and fast consumption of glucose is the reason for increased foaming and declined FK520 production. Therefore, a fed-batch fermentation strategy was developed to reduce the accumulation of acetate. After optimization, the maximum acetate concentration dropped from 320 mg.L-1 to 157 mg.L- 1, decreased by 50.8%, and the maximum foam height reduced from 5.32 cm to 3.74 cm, decreased by 29.7%, while the maximum FK520 production increased from 375 mg.L-1 to 421 mg.L-1, improved by 12%. (C) 2015 The Chemical Industry and Engineering Society of China, and Chemical Industry Press. All rights reserved