Objective To establish an animal model of high altitude pulmonary edema (HAPE) in the plateau field laboratory, and explore the preventive effect of Betelnut polyphenols on HAPE. Methods Thirty-six Wistar rats were randomly divided into 6 groups (6 each): control group (4 ml normal saline), HAPE model group (4 ml normal saline), rhodiola group(280 mg/kg Rhodiola capsule) and Betelnut polyphenol group with different doses (400, 800 and 1200 mg/kg Betelnut polyphenol).All animals except those in control group were rushed into the high altitude laboratory at an altitude of 4010 m 3 days after preventive administration and assisted with exhaustive exercise on the running platform, the animals in control group kept in the 940th Hospital of PLA Joint Logistics Support Force. One hour after last administration, abdominal aortic blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The arterial oxygen saturation (SatO₂), blood pH, arterial carbon dioxide partial pressure (PaCO₂), arterial oxygen partial pressure (PaO₂), plasma actual bicarbonate (HCO₃^-), standard bicarbonate (SBC) and other blood gas indexes were measured with blood gas analyzer; lung water content (LWC), protein content of BALF and the activity of superoxide dismutase (SOD), contents of malondialdehyde (MDA) and glutathione (GSH) in lung tissues were measured;pathological structure of lung tissue was observed by HE staining. Results Compared with control group, the levels of SatO₂, pH value, PaO₂, PaCO₂, PO₂/FIO₂, SBC, TCO₂, and HCO₃^- decreased significantly in HAPE model group (P<0.05 or P<0.01), the levels of LWC and BALF protein increased significantly (P<0.01), SOD activity and GSH content of lung tissues decreased, and MDA content of lung tissues increased (P<0.05), the normal structure of lung tissue was destroyed. Compared with HAPE model group, the levels of SatO₂ and pH value of low, medium and high dose Betelnut polyphenols groups increased significantly (P<0.05 or P<0.01), the levels of LWC and BALF protein in those groups decreased (P<0.01), the SOD activity and GSH content in lung tissues of medium and high dose Betelnut polyphenols groups increased significantly (P<0.01), the MDA content in high dose Betelnut polyphenols group decreased significantly (P<0.05). HE staining showed that, the alveolar wall was thickened significantly,the alveolar cavity was narrowed, red blood cells and pink protein existed and accompanied with inflammatory cell infiltration in HAPE model group; after preventive administration, the alveolar structure of rats in the low, medium and high doses of Betelnut polyphenol groups tended to be complete, the alveolar wall became thinner, the exudation in the alveolar cavity decreased or even disappeared, and the inflammatory cells decreased. Conclusions The HAPE rat model can be successfully established by rushing to high altitude and exhausting exercise with running platform, and the preventive administration of Betelnut polyphenol 800 and 1200 mg/kg can effectively prevent the occurrence of HAPE.