This paper is concerned with the optimization of effect factors for mycelial growth and exopolysaccharide production by Schizophyllum commune by one-factor-at-a-time and orthogonal methods. The one-factor-at-a-time method was adopted to investigate the effects of six different compounds (sodium carboxymethylcellulose, l-glutamic acid, V-B1, naphthalene acetic acid, oleic acid, and Tween 80) on mycelial growth and exopolysaccharide production. Among these factors, oleic acid, V-B1 and Tween 80 were identified to be the most important factors. Subsequently, the concentration of oleic acid, V-B1 and Tween 80 were optimized using the orthogonal matrix method. The effects of the factors on the mycelial growth of S. commune were in the order of oleic acid > V-B1 > Tween 80, and those on exopolysaccharide production were in the same order. The optimal concentration for mycelia and exopolysaccharide were determined as oleic acid 0.1% (v/v), V-B1 0.5 mg/L, and Tween 80 6 mg/L. The subsequent verification experiments confirmed the validity of the models. Under this optimized conditions in shake flask culture, the mycelial yield and exo-biopolymer production were 25.93 and 2.79 g/L, respectively, which were considerably higher than those obtained in the preliminary studies. The result was further confirmed in a 7-L fermentor experiments.