Objective To explore the effect of prolonged low-flow oxygen inhalation time through nasal cannula on systemic inflammatory response, intrapulmonary shunt and prognosis after hepatectomy under general anesthesia in hepatocarcinoma patients with hepatopulmonary syndrome. Methods Seventy-two patients of hepatocarcinoma with hepatopulmonary syndrome, who underwent hepatectomy in Anesthesia Department of Southwest Hospital of Army Medical University (Third Military Medical University) from Jan. 2017 to Dec. 2018, were enrolled in this study. Their American Society of Anesthesiologists (ASA) grades were classified as grade Ⅱ or Ⅲ. All patients were randomized into control group (n=36) and research group (n=36). The patients in the control group inhaled low-flow oxygen (2-3 L/min) through nasal cannula for 8 h after operation, and those in the research group for 48 h. Before anesthesia, and immediately, 8 h, 24 h, 48 h and 72 h after operation, the radial artery blood gas analysis was conducted to record arterial partial pressure of oxygen (PaO₂) and alveolar-arterial oxygen pressure difference ([A-a]DO₂). At each time point, tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS) in peripheral blood and fractional exhaled nitric oxide (FeNO) were measured as well. C-reactive protein (CRP), white blood cell count and neutrophil proportion in peripheral blood were measured 48 h after operation. The incidence of postoperative pulmonary complications and hospital stay were compared between the two groups. Results In the two groups, the PaO₂ values were significantly higher immediately and 8 h after operation versus before anesthesia, and the (A-a)DO₂ values were significantly lower (all P<0.05). At 24 h and 48 h after operation, the PaO₂ values in the research group were significantly higher than that before anesthesia, and the (A-a)DO₂ values were significantly lower than that before anesthesia (all P<0.05); while those in the control group showed the opposites (all P<0.05); and the PaO₂ values in the research group were significantly higher than those in the control group, and (A-a)DO₂ values were significantly lower (all P<0.05). The levels of LPS, TNF-α and FeNO in the research group 8, 24 and 48 h after operation were significantly lower than those before anesthesia (all P<0.05), while those in the control group 24 and 48 h after operation were significantly higher than those before anesthesia (all P<0.05). The levels of LPS, TNF-α and FeNO in the research group were significantly lower than those in the control group 24 and 48 h after operation (all P<0.05). At 48 h after operation, CRP level, white blood cell count and neutrophil proportion in the research group were significantly lower than those in the control group (all P<0.05). The incidence of postoperative pulmonary complications in the research group (1/36) was lower than that in the control group (6/36), and the hospital stay ([5.2±2.3] d) was shorter than that in the control group ([7.8±3.2] d), and the differences were statistically significant (both P<0.05). Conclusion Prolonged oxygen inhalation time (48 h) can effectively alleviate systemic inflammatory response, reduce intrapulmonary shunt and the incidence of pulmonary complications, thus facilitating postoperative recovery after hepatectomy in patients of hepatocarcinoma with hepatopulmonary syndrome.