Abstract: Objective To establish a rat model of heatstroke complicated by endotoxemia for studying the pathogenesis of severe heatstroke. Methods Male specific pathogen-free Wistar rats were randomly assigned into 4 groups, namely normother-mic saline group (group C), heat exposure saline group (group H), normothermic LPS group (group L), and heat exposure LPS group (group HL). The rectal temperature (Tr), heart rate (HR), mean arterial pressure (MAP), and respiratory rate (RR) of the rats receiving different treatments were continually monitored and their white blood cell count (WBC) and histology of the lungs were observed at 0, 40, 80 and 120 min after the treatments. Results The rats in HL-Group displayed significantly higher Tr (43.04±0.11 ℃), HR (660±42 beats/min), and RR (150±11/min) but lower MAP (49.0±3.5 mmHg) as compared with the C Group. There were significant differences in the values of Tr, HR, RR and MAP between HL and group L and in HR and MAP between H groups HL and. The rats in group H displayed significantly higher WBC than group C. In contrast, the rats in L groups HL and had significantly lower WBC. LPS injection and heat stress induced pulmonary edema and features characteristic of acute microvascular lung injury in the rats. Conclusion The rat model established by LPS injection and heat stress can successfully mimic the development of severe heatstroke after LPS challenge and heat stress, and provides a suitable model for studying the primordial role of the lungs in the pathogenesis of severe heatstroke.