Hyaluronic acid (HA) is a natural biopolymer with unique physiochemical and biological properties and finds a wide range of applications in biomedical and cosmetic fields. It is important to increase HA production to meet the increasing HA market demand. This work is aimed to model and optimize the amino acids addition to enhance HA production of Streptococcus zooepidemicus with radial basis function (RBF) neural network coupling quantum-behaved particle swarm optimization (QPSO) algorithm. In the RBF-QPSO approach, RBF neural network is used as a bioprocess modeling tool and QPSO algorithm is applied to conduct the optimization with the established RBF neural network black model as the objective function. The predicted maximum HA yield was 6.92 g/L under the following conditions: arginine 0.062 g/L, cysteine 0.036 g/L, and lysine 0.043 g/L. The optimal amino acids addition allowed HA yield increased from 5.0 g/L of the control to 6.7 g/L in the validation experiments. Moreover, the modeling and optimization capacity of the RBF-QPSO approach was compared with that of response surface methodology (RSM). It was indicated that the RBF-QPSO approach gave a slightly better modeling and optimization result compared with RSM. The developed RBF-QPSO approach in this work may be helpful for the modeling and optimization of the other multivariable, nonlinear, time-variant bioprocesses. (C) 2009 American Institute of Chemical Engineers Biotechnol. Prog., 25: 1819-1825, 2009