Acute alcoholism is a common pathological state caused by excess intake of ethanol in a short period. It leads to multiple organ functional damage such as central nervous system depression, respiratory and circulatory system dysfunction, metabolism and immune system abnormal. In order to study the reason of death caused by acute alcoholism, we developed a mouse model of acute alcoholism by intraperitoneal injection method. We reported for the first time that HMGB1 played an important role in acute alcoholism. HMGB1 was released and detected in the serum as early as 0.5 h after the intraperitoneal injection of ethanol. Then HMGB1 induced subsequent acute systemic inflammatory response. We further provided evidences indicating that anti-HMGB1 antibody could effectively protect mouse from acute alcohol. This protection was achieved by significantly reducing HMGB1 release and suppressing systemic inflammation.