BACKGROUND Preoperative therapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, there are few indicators that can predict the effect of preoperative chemotherapy accurately. AIM To investigate whether the increase in serum alpha-fetoprotein (AFP) can predict better efficacy of preoperative chemotherapy. METHODS This was a retrospective study. We analyzed 125 patients admitted between 2017 and 2019 with locally advanced rectal cancer. All patients received six cycles of preoperative chemotherapy (mFOLFOX6 every 2 wk). Serum AFP of 26 patients rose slightly after three or four cycles of chemotherapy, and fell to normal again within 2 mo. The other 99 patients had a normal level of serum AFP during chemotherapy. Patients were divided into two groups (AFP risen and AFP normal). According to postoperative pathology, we compared tumor regression and complete response rate between the two groups. The primary outcome measure was the tumor regression grade (TRG) after chemotherapy. The difference in pathological complete response between the two groups was also investigated. RESULTS There were no tumor progression and distant metastasis in both groups during preoperative chemotherapy. Patients in the AFP risen group achieved better TRG 0/1 than those in the AFP normal group (61.5% vs 39.4%). The increase in AFP was a significant predictor for better tumor regression [chi(2) = 4.144, odds ratio (OR) = 2.666, P = 0.04]. In the AFP risen group, the complete response rate was 30.8%, which was higher than in the AFP normal group (30.8% vs 12.1%, chi(2) = 4.542, OR = 3.251, P = 0.03). CONCLUSION Patients with a slight increase in serum AFP can achieve better tumor regression during preoperative chemotherapy, and are more likely to achieve pathological complete response. (c) The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.