Objective To compare three rat models of acute stress response and to explore an ideal experimental rat model for research of acute stress response. Methods A total of 40 clean grade male SD rats were randomly (by random number) divided into 4 groups (n=10 each):Normal group (group I), caudal trunk transection group (group II), burn group (group III), and amputation group (group IV). The group I received no special treatment, the group II received inferior caudal trunk transection at the level between sacral spinal nerve 3 and 4 (S3, S4), the group III was inflicted with 30% total body surface area (TBSA) grade 3 burn on the back, and the group IV had an amputation of the left lower limb as severe traumatic stress. Rats in each group were killed at 30 minutes after treatment and blood samples were collected for measuring serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels by ELISA. The c-fos protein expression in hypothalamic tissue was examined by immunohistochemistry. Results Compared with the group I, serum ACTH and CORT levels, and hypothalamic expression of c-fos protein in the group II, III, IV were significantly increased (P<0.05).Compared with the group III, serum ACTH and CORT levels, and hypothalamic expression of c-fos protein were significantly higher in the group II and IV (P<0.05), while there was no significant difference between the group II and IV (P>0.05). Conclusions The preparation of acute stress response model induced by inferior caudal trunk transection has simple operation steps and produces a traumatic injury to a similar degree, and quite well reflects the acute stress response in humans caused by sudden accident. Therefore it is a quite good method to establish acute stress response and deserves further investigation.