In the present study, we investigated the anti-inflammatory activity of water-soluble polysaccharide of Agaricus blazei Murill (WSP-AbM) on ovariectomized osteopenic rats. The rats were administered orally WSP-AbM (200 mg/kg BW) for 8 weeks. Subsequent serum maleic dialdehyde (MDA) level, total antioxidant status (TAOS), nuclear factor kappa B (NF- κ B) level, polymorphonuclear (PMN) cells level, interleukin-1 β (IL-1 β ) level, inducible nitric oxide synthase (iNOS) level, tumor necrosis factor- α (TNF- α ) level, adhesion molecule (ICAM-1), and cyclooxygenase-2 (COX-2) were determined by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. WSP-AbM administration markedly (P < 0.05) decreased serum IL-1 β and TNF- α levels and the expressions of ICAM-1, COX-2, and iNOS NF- κ B compared with OVX rats. WSP-AbM administration alsomarkedly (P < 0.05) decreased PMN infiltration. In conclusion, we observed that WSP-AbM supplementation had anti-inflammatory effects in a model of osteoporosis disease.