Objective To investigate the relationship of 5-HT in gastrointestinal tract with liver regeneration using 5-HTSUB>4/SUB> receptor regulator in rats after partial hepatectomy (PH). Methods Adult SD rats (n = 60) with PH were divided into three groups: control, cisapride and GR113808 group. After PH, Cisapride (a 5-HTSUB>4/SUB> receptor agonist, 10 mg/kg, twice per day, ig) and GR113808 (a 5-HTSUB>4/SUB> receptor antagonist, 3 mg/kg, twice per day, ip) were administered to the corresponding groups, respectively. Four kind of tissues (blood, stomach, small intestine and liver) were taken out at 0 hour, 24 hours, 48 hours, 72 hours, respectively, then the ratios of liver mass to body weight was accounted. 5-HT immunoreactive cells (5-HTIR cells) in stomach and small intestine were detected by immunohistochemical technique. The average gray level of 5-HTIR cells was detected by image analysis system. The plasma 5-HT level was determined by enzyme-linked immunosorbent assary(ELESA). The numbers of argyrophil nucleolar organizer regions(AgNORs) were detected by silver staining technique. Results Compared with the control, 1. The amounts of 5-HTIR cells in both stomach and small intestine decreased at 48-72 hours (EM>P/EM><0.05), the gray level of 5-HTIR cells increased significantly at 24-72 hours when plasma 5-HT level increased significantly(P<0.05), both the ratios of liver mass to body weight and AgNORs particles numbers in liver increased significantly at 48-72 hours(P<0.05), in cisapride rats with PH; 2. The amounts of 5-HTIR cells in both stomach and small intestine had not statistical difference at 24-72 hours when both the gray level of 5-HTIR cells and plasma 5-HT level decreased significantly (EM>P/EM><0.05 or EM>P/EM> <0.01), the ratios of liver mass to body weight decreased significantly at 4872 hours, and AgNORs particle numbers in liver decreased significantly at 24-72 hours (EM>P/EM><0.05 or EM>P /EM> <0.01), in GR113808 rats with PH. Conclusion Secretion of 5-HT in gastrointestinal tract was changed by 5-HTSUB>4/SUB> receptor regulator, which resulted in the changes of both the ratios of liver mass to body weight and the transcriptional activity of regenerating hepatocytes. In conclusion, 5-HT from gastrointestinal tract can significantly promote hepatocyte proliferation after partial hepatectomy.