The cell growth and total accumulation of bioactive metabolites were significantly improved by Cu(2+) addition during the submerged fermentation of medicinal mushroom Ganoderma lucidum. A mathematical model, constructed by response surface methodology combination with full factorial design, was applied to study the synergic effect of Cu(2+) addition concentration and addition time. The optimal Cu(2+) inducement strategy for the cell growth were different from those for the biosynthesis of ganoderic acid (GA) and Ganoderma polysaccharide. A multiple additions strategy of Cu(2+) by adding each 1 mM Cu(2+) on day 2, 6, 8 and 2 mM Cu(2+) on day 4 was developed to enhance total accumulation of GA and extracellular polysaccharides. The highest GA content reached 3.0 +/- 0.1 mg per 100 mg DW, which was increased by 76.5% and 33.9% compared with the control without Cu(2+) addition and the peak value predicted by the constructed mathematical model, respectively. While, relatively higher addition concentration of Cu(2+) (i.e., 5 mM) on the culture of day 4 led to higher content and total production of intracellular polysaccharides.