Objective To study the roles of ethyl pyruvate ( EP ) in spinal cord edema after spinal cord injury ( SCI ) and in spinal cord astrocytic swelling after oxygen-glucose deprivation and reoxygenation ( OGD/R) in vitro in rats. Methods After SCI models were established in adult Sprague-Dawley ( SD ) rats, an intraperitoneal injection of EP was conducted to inhibit high mobility group box-1 ( HMGB1 ). Effects of EP on spinal cord edema, HMGB1 expression and astrocyte activation ( glial fibrillary acidic protein ( GFAP ) expression) in SCI rats were analyzed. Spinal cord astrocytes were cultured in post-natal SD rats and incubated under OGD/R procedure. Effects of EP on cell swelling, expression of HMGB1, aquaporin-4 ( AQP4 ) and toll-like receptor 4 ( TLR4 ) , and nuclear expression of nuclear factor-kappa B ( NF-κB ) in spinal cord astrocytes were observed. Results The water content in the spinal cord was increased significantly more at 1 d after SCI than at 12 h and 3 d ( P ＜0.05 ). Intraperitoneal injection of EP at 50 mg/kg reduced spinal cord water content, HMGB1 expression and astrocyte activation ( GFAP expression ) in SCI rats signif-icantly more than that at 25 mg/kg or 100 mg/kg ( P ＜0.05 ). The volume of spinal cord astrocytes cultured in vitro after OGD 6 h/R 24 h was significantly greater than that after OGD 6 h/R 6 h or OGD 6 h/R 12 h ( P ＜0.05 ). EP at 12 μmol/L reduced cell swelling, decreased expression of HMGB1, AQP4 and TLR4, and downgraded nuclear expression of NF-κB in spinal cord astrocytes after OGD/R significantly more than EP at 6 μmol/L( P ＜0.05). Conclusion EP may reduce early spinal cord edema after SCI, attenuate spinal cord astrocyte swelling and decrease AQP4 expression after OGD/R in vitro by inhibiting HMGB1 in rats.