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Background Numerous studies suggest that intravenous propofol is superior to inhaled volatile anesthetic. This study compared the changes in the endoplasmic reticulum (ER) stress of cancer cells and lymphocytes after propofol- and sevoflurane-based anesthesia during breast cancer surgery. Methods We randomized 53 patients undergoing breast cancer surgery to propofol (n = 28) and sevoflurane (n = 25) anesthesia groups. Blood samples were obtained immediately before inducing anesthesia, and 1 and 24 h postoperatively. Human breast cancer cell lines were cultured and treated with patient plasma, and the frequency of C/EBP homologous protein (CHOP) on the cancer cell lines and lymphocytes was measured. The neutrophil-to-lymphocyte ratio in plasma was evaluated in both groups. Results The CHOP expression on breast cancer cell lines did not differ between the groups (P = 0.108), although it decreased significantly over time (P = 0.027). The CHOP expression on lymphocytes was comparable between the groups (P = 0.485), and was the neutrophil-to-lymphocyte ratio (P = 0.501). Conclusions Propofol-based anesthesia did not induce greater ER stress than sevoflurane-based anesthesia during breast cancer surgery. The ER stress of cancer cells did not differ according to the type of anesthesia during breast cancer surgery.