Mycophenolic acid (MPA) is a secondary metabolite of Penicillium brevicompactum with diverse biological properties and clinical applications mainly as an immunosuppressive agent. In this study, a complex medium for MPA production by P brevicompactum ATCC 16024 was optimized by the orthogonal methodology employing a four factorial design at four levels in shake flasks. The optimized medium was then tested for mycophenolic acid production in 5 L fermentors. It was found that conventional stirred-tank fermentor was difficult to operate with the fungal mycelia growing uncontrollable everywhere in the fermentor, causing a relatively low MPA productivity. To overcome this problem, spores of P brevicompactum were immobilized in a rotating fibrous-bed (RFB) in the bioreactor. After spore germination, essentially all mycelia were attached to the RFB and the fermentation broth remained clear throughout the batch fermentation. The immobilized-cell fermentation in the RFB bioreactor reached a high MPA concentration of 5.7 g/L in about 14 days. The advantages of the RFB fermentation also include ease of product purification from the cell-free fermentation broth and possible repeated use of the same mycelial cells for the production of the secondary metabolite without requiring growing new cell biomass in extended fermentation operation, which can reduce the fermentation time for each production batch and further increase the volumetric productivity of MPA in the fermentation. (c) 2006 Elsevier Inc. All rights reserved.