Scale-up of a liquid static culture process was studied for hyperproduction of ganoderic acid (GA) by a famous Chinese traditional medicinal mushroom, Ganoderma lucidum. Initial volumetric oxygen transfer coefficient (K(L)a) and area of liquid surface per liquid volume (A(s)) were identified as key factors affecting cell growth and GA accumulation in liquid static cultures of G. lucidum, on the basis of which a multilayer static bioreactor was designed. At a low initial K(L)a level of 2.1 h(-1), a thick layer of white mycelia was formed on the liquid surface, and an optimal production of total GA (i.e., GA production in the liquid and on the liquid surface) was obtained. Both the formation of white mycelia and production of GA on the liquid surface were enhanced with an increase of A(s) within the range as investigated (0.24-1.53 cm(2)/mL). At an A(s) value of 0.90 cm(2)/mL, the total GA production reached maximum. A successful scale-up from a 20-mL static T-flask to a 7.5-L three-layer static bioreactor was achieved based on initial K(L)a. The maximum biomass (20.8 +/- 0.1 g DW/L), GA content (4.96 +/- 0.13 mg/100 mg DW), and total GA production (976 +/- 35 mg/L) were attained in static bioreactors. Not only GA content but also its production obtained in this work were the highest ever reported.