BACKGROUND This experiment was designed to investigate the effect of substance P (SP) on liver regeneration after partial hepatectomy in a rat model. MATERIAL AND METHODS Male Sprague-Dawley rats were used in this experiment and were divided into an untreated sham group (n=3); a saline group (control group) given a saline injection after hepatectomy (n=4); and an SP group (experimental group) given SP injection after hepatectomy (n=4). The experiments were repeated 3 times in the sham, saline, and SP groups (days 1, 2, and 3). Liver function tests were performed on the serum. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA), Ki-67, and CD133, and western blotting was performed for PI3KC, Akt, p38, ERK, and mTOR. RESULTS Liver function test results indicated higher levels in the saline group than in the SP group at day 1. However, the difference gradually disappeared at days 2 and 3. PCNA and Ki-67 were more highly expressed in the SP group than in the saline and sham groups at day 1. CD133 was strongly expressed in the SP group at day 2 compared to that in the sham and saline groups. The changes in mTOR/Akt/PI3KC pathway protein and ERK/p38 signaling protein expression levels were not significantly different among groups. CONCLUSIONS SP accelerated the regeneration stage after hepatectomy in a rat model.