Stage IV colorectal cancer (CRC) patients with liver metastasis undergoing potentially curative surgery represent a subgroup of patients with a relatively good prognosis. In this study, we aimed to evaluate the performance of mSEPT9 to monitor response to treatment and predict prognosis.In total, we recruited 51 stage IV CRC patients with liver metastasis, including 20 patients who underwent simultaneous surgery and 31 patients who underwent staged surgery. We measured the blood levels of mSEPT9 and CEA prior to surgery and then seven days after surgery.mSEPT9 and CEA were detected prior to surgery in 92.2% (47/51) and 70.6% (36/51) of patients, respectively. Following simultaneous and staged surgery, levels of mSEPT9 fell significantly by 923-fold (P<0.001) and 11-fold (P<0.001), respectively. Levels of CEA also fell significantly by 17-fold (P<0.001) and 1.7-fold (P<0.01) following simultaneous and staged surgery, respectively. The mean percentage reduction of mSEPT9 levels after simultaneous surgery (12.3%) was significantly lower than that of staged surgery (33.8%) (P<0.001) while the mean percentage reduction of CEA levels after simultaneous surgery (35.5%) were significantly lower than that of staged surgery (64.6%) (P<0.05). The levels of mSEPT9 in the blood were quantitatively correlated with tumor burden. Survival analysis showed that patients who tested negative for mSEPT9 pre- and post-surgery had a better survival rate than those who tested positive, thus suggesting that mSEPT9 can act as a prognostic indicator.mSEPT9 showed good quantitative efficacy, higher applicability, and sensitivity, than CEA in assessing treatment response and prognosis prediction in patients with stage IV CRC and liver metastasis.Copyright © 2021 Elsevier Inc. All rights reserved.