Objective To examine the effects of ulinastatin (UTI) on cardiac dysfunction in mice with heat stroke and its possible mechanism. Methods 20 mice were divided into four groups randomly: room temperature plus normal saline (Sham+NS), room temperature plus UTI (Sham+UTI), heat stress plus normal saline (HS+NS), heat stress plus UTI (HS+UTI), 5 each. 105U/kg UTI was delivered by intraperitoneal injection before the onset of the heat stress. Room temperature groups were housed at room temperature (23.0±0.5℃), while heat stress groups were kept in an incubator at 36.5±0.5℃ and humidity of 65.0%±2.0%. The rectal temperature (Tr) reaching 42℃ was taken as severe heat stroke, and the time in two heat stress groups was recorded. The mice were transferred to the room temperature (23.0±0.5℃) for natural cooling after the heat stroke onset. 6 hours after the treatment, cardiac output (CO) was ultrasonographically detected, the myocardium was separated for histopathological examination and the expression of total p38 and phosphorylated p38 (p-p38) was determined by Western blotting. Results The time to reach 42℃ in HS+UTI group was significantly prolonged (P=0.044). Compared with the Sham+NS group, the CO in HS+NS and HS+UTI group decreased significantly (P=0.017), and the score of myocardial inflammation (P<0.001) and p-p38/p38 ratio (P<0.001) increased. The CO was significantly higher in HS+UTI group than in HS+NS group (P=0.030), and the score of myocardial inflammation (P<0.001) and p-p38/p38 ratio (P=0.001) were significantly lower. Conclusion Ulinastatin might improve the cardiac function in mice with heat stroke by decreasing the p-p38 and alleviating the inflammation response. DOI: 10.11855/j.issn.0577-7402.2017.04.04