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.