A new polysaccharide fraction (CCPP-1) was obtained from Craterellus cornucopioides. CCPP-1 had an average molecular weight of 9.2 × 105 Da, which was mainly composed of mannose, glucose, xylose, arabinose, fructose in molar ratio of 0.7:0.05:0.18:1:0.05. Results of structural characterization revealed that the dominant linkage types of CCPP-1 were →3, 6)-Manp(1→, T-Araf, →4, 6)-Manp (1→, →5)-Araf (1→ and →3)-Araf (1→. Interesting, in vitro antioxidant activities assays showed that CCPP-1 possessed strong scavenging abilities on DPPH and ABTS radicals. The oxidative hemolysis induced by AAPH in mice erythrocytes was effectively reversed by incubation with CCPP-1. CCPP-1 significantly prevented AAPH-induced intracellular reactive oxygen species (ROS) generation. Moreover, CCPP-1 could significantly restore AAPH-induced increase of intracellular antioxidant enzyme glutathione peroxidase (GPx) and catalase (CAT) activities to normal level, as well as inhibit intracellular malondialdehyde (MDA) formation. Therefore, CCPP-1 could protect against AAPH-induced oxidative-stress in erythrocytes, which would be explored as naturally potential antioxidant agent applied in food and cosmetic fields.