Objective: To study the clinical effect of mild hypothermia therapy with different durations in patients with severe traumatic brain injury (sTBI). Methods: A total of 90 patients with sTBI admitted to ICU of The First People’s Hospital of Hefei and Binhu Hospital from August 2016 to December 2017 were selected prospectively as the subjects, and all patients were randomly divided into a long-term mild hypothermia group (group A, n=30), a short-term mild hypothermia group (group B, n=30), and a conventional group (group C, n=30). Group A was given only basic treatment. Group B was treated with mild hypothermia after admission and the body temperature was controlled at 33–35 ℃, lasting 5 days. The group C was treated with mild hypothermia after admission and the temperature was controlled at 33–35 ℃ for 2 days. The clinical effects of the 3 groups were compared in the 6th day. Results: There was no significant difference in intracranial pressure (ICP) between the three groups before treatment (P>0.05), and the ICP was statistically significant on the 6th day after injury (P<0.05). The APACHE II scores of the 3 groups on the 6th day after injury were statistically significant (P<0.05), and the group C on the 6th day after injury was higher than that of the group B (P<0.05). The incidence of complications in the group A was higher than that in the group B and the group C (P<0.05). The incidence of complications in the group C was higher than that in group B (P>0.05), but the mortality in the group A was higher than that in the group B (P<0.05). The mortality rate in the group C was higher than that in the group B (P>0.05). Conclusion: The effect of mild hypothermia therapy on patients with sTBI is significant. Although long-term mild hypothermia therapy could not reduce the mortality rate significantly in a short period of time, it could reduce ICP and the risk of long-term death significantly. The incidence of patient complications is no significant increase.