To explore the mechanism of Guizhi Fuling Pill in the treatment of uterine leiomyoma model rats.Methods:A total of 60 adult female SD rats were randomly divided into 4 groups:a blank (Control) group (n=15)，a model (Hys) group (n=15)，a low dose Guizhi Fuling pill (G-L) group (n=15) and a high dose Guizhi Fuling Pill (G-H) group (n=15).Except for the sham operation group，the other 3 groups were modeled by uterine leiomyoma.G-L group and G-H group received 1.32 g/mL and 2.64 g/mL Guizhi Fuling Pill suspension 1 mL respectively，and the rats in the control group and Hys group were given the same dose of normal saline once a day for 8 weeks.The coefficients of uterus and ovary were recorded，the morphological changes of uterus were observed by HE staining，the ultrastructural changes of uterus were observed by transmission electron microscope，the contents of E2，P and ER in uterine tissue were detected by ELISA method，and the expression of PI3K/Akt signal pathway protein in uterine tissue was detected by Western Blot method.Results:Compared with Control group，the coefficient of uterus and ovary，the content of E2，P，ER and the expression of anti-apoptotic protein PI3K and p-Akt increased (P<0.05) and the expression of pro-apoptotic protein Caspase-3 decreased (P<0.05) in Hys group.The above-mentioned indexes were improved in G-L group and G-H group (P<0.05)，but the expression of anti-apoptotic protein PI3K and p-Akt in G-H group was significantly better than that in G-L group (P<0.05).The morphological observation of HE staining and transmission electron microscope showed that the uterine smooth muscle of Hys group thickened，the cell boundary was not clear，the nuclear pyknosis was oval or abnormal，the mitochondria in the cytoplasm swelled，part of the crest ruptured and disappeared，the rough endoplasmic reticulum dilated，the muscle fibers were disordered，and obvious inflammatory cell infiltration could be seen.The arrangement of uterine smooth muscle cells in G-Lgroup was more orderly than that in Hys group，the smooth muscle layer was still thicker，the infiltration of inflammatory cells was less than that in Hys group，the nucleus was slightly larger，and the swelling of mitochondria and dilatation of rough endoplasmic reticulum in G-L group were less than those in Hys group.The arrangement of uterine smooth muscle cells in G-H group was more orderly and compact than that in Hys group，only slight inflammatory cell infiltration，no obvious proliferation of smooth muscle layer，normal smooth muscle nucleus，mitochondria and rough endoplasmic reticulum were close to normal.Conclusion:Guizhi Fuling Pill can effectively improve the morphological indexes of uterine leiomyoma model rats，and its mechanism may be related to the activation of PI3K/AKT pathway，down-regulation of E2，P，ER expression and up-regulation of Caspase-3 expression.