The effect of polysaccharide extract isolated from Ganoderma lucidum (Gl-PS) on rat cortical neuronal cultures exposed to hypoxia/reoxygenation (H/R) was studied in vitro. Gl-PS (1, 10, 100 microg/ml) increased neuron viability following H/R as measured by the inhibition of MTT reduction. Gl-PS also significantly reduced malondialdehyde content and reactive oxygen species production and increased the manganese superoxide dismutase (Mn-SOD) activity; furthermore, the translocation of nuclear factor-kappa B induced by H/R was blocked. These findings suggest that Gl-PS might be useful in treating H/R-induced oxidative stress and Mn-SOD might play a critical role in the neuroprotective effect of Gl-PS against H/R injury.