Abstract: Objective To investigate the risk and predictive factors of apatinib-induced hand-foot syndrome (HFS) in patients with colorectal cancer. Methods A retrospective analysis was conducted on 219 colorectal cancer patients treated with apatinib at the Sanmen Bay Branch of the First Affiliated Hospital of Zhejiang University School of Medicine from January 2019 to June 2023. Based on the occurrence of HFS, patients were divided into an occurrence group and a non-occurrence group. Baseline characteristics and laboratory test results of patients were compared between the two groups, and logistic regression analysis was performed to identify factors associated with HFS. Results After excluding 12 patients lost to follow-up due to death or other reasons, a total of 207 patients were included in the final analysis. Among them, 45 patients (21.74%) were in the occurrence group, and 162 patients (78.26%) were in the non-occurrence group. The proportion of patients receiving an apatinib dose of 500 mg was higher in the occurrence group compared with the non-occurrence group (P ＜ 0.05). Additionally, the occurrence group showed significantly higher levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBil), and white blood cell (WBC) count (P ＜ 0.05). Incorporating the variables with statistically significant differences from above into multivariate logistic regression analysis, the results show that an apatinib dose of 500 mg (OR=2.568, 95% CI: 1.159~5.689), WBC level (OR=1.052, 95% CI: 1.007~1.098), ALT level (OR=1.141, 95% CI: 1.067~1.220), AST level (OR=1.181, 95% CI: 1.064~1.310), and TBil level (OR = 1.228, 95% CI: 1.139 ~ 1.325) were identified as risk factors for apatinib-induced HFS (P ＜ 0.05). Conclusion Patients receiving an apatinib dose of 500 mg or those with higher WBC, ALT, AST, and TBil levels are more susceptible to developing HFS following apatinib treatment. Therefore, for such patients, a comprehensive assessment of HFS risk should be conducted, and treatment plans should be adjusted promptly to prevent HFS occurrence.