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Objectives: To investigate the clinical effects of TP-based hyperthermic intraperitoneal chemotherapy (HIPEC) on the levels of antigen cluster protein 133 (CD133) and human epididymal secretory protein 4 (HE4) in patients with advanced epithelial ovarian cancer (EOC). Methods: A total of 104 patients with advanced EOC hospitalized in Affiliated Hospital of Hebei Engineering University from April 2015 to December 2018 were assigned to two groups using a random number table. A control group (n =52) treated by the conventional postoperative TP regimen and an observation group (n =52) receiving HIPEC in addition to the conventional postoperative TP regimen. CD133 and HE4 expression in serum, overall response rate (ORR), long-term efficacy, and incidence of drug toxicity were measured for comparative analysis. Results: The serum levels of CD133 and HE4 expression in the observation group were lower than in the control group (P < 0.005, respectively); the observation group surpassed the control group in ORR, 2-year survival, and progression-free survival (PFS) (P < 0.005, respectively); however, the two groups had no statistically significant difference in the incidence of drug toxicity (P > 0.05). Conclusions: TP-based HIPEC can effectively inhibit CD133 and HE4 expression in advanced EOC, which thereby improves the clinical efficacy and encourages longer survival. [ABSTRACT FROM AUTHOR]