Objective: To study the expression and significance of Smac and caspase-3 in proliferative phase, atypical hyperplasia phase, and endometrial adenocarcinoma. Methods: Immunohistochemical SP method was used to detect the expression of Smac and caspase-3 in 95 cases of paraffin-embedded specimens (17 cases in the proliferative endometrium group, 20 cases in the endometrial atypical hyperplasia group, and 58 cases in the endometrial adenocarcinoma group). Results: The positive expression rates of Smac and caspase-3 in the three groups were successively decreased, and the difference was statistically significant (P<0.05). In endometrial adenocarcinoma, the positive expression of Smac was significantly different from the histopathological staging, histological grade, and metastasis of lymph nodes (P<0.05), but was not related to age and myometrial infiltration depth (P>0.05). The positive expression and histological grading of caspase-3 were statistically significant (P<0.05), but not related to age, surgical pathological stage, myometrial infiltration depth, and lymph node metastasis (P>0.05). The expression of Smac and caspase-3 in endometrial adenocarcinoma showed a significant positive correlation (P<0.05). Conclusion: In endometrial adenocarcinoma, Smac and caspase-3 may be involved in its malignant progression. Detection of Smac and caspase-3 expression in different endometrial tissues is of great significance to the study of the occurrence and development of endometrial adenocarcinoma.