Advanced castration-resistant prostate cancer has high mortality rates and limited treatment options. Novel therapies are needed to better contend with this disease. Polysaccharide-K® (PSK), an extract of the mushroom Trametes versicolor, has immunomodulatory and tumor suppressive activities. PSK is used in Asia as a cancer immunotherapy. However, its benefit in combination with taxanes for prostate cancer is unknown. We examined whether PSK would enhance docetaxel-induced apoptosis and augment anti-tumor immune responses in orthotopic tumors using transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2-bearing mice. Combining PSK with docetaxel induced significantly higher tumor suppression than either treatment alone (p<0.05), including a reduction in tumor proliferation and enhanced apoptosis. Combined PSK and docetaxel treatment led to a lower decrease in number of white blood cells than docetaxel alone, an effect accompanied by increased numbers of tumor-infiltrating CD4+ and CD8+ T cells. PSK with or without docetaxel significantly enhanced mRNA expression of IFN-γ compared to control, but did not significantly alter T-regulatory FoxP3 mRNA expression in tumors. PSK also augmented docetaxel-induced splenic natural killer cell cytolytic activity against YAC-1 target cells (p=0.045). This study is the first to show that PSK enhances docetaxel-induced prostate cancer tumor suppression, apoptosis and antitumor responses.