BACKGROUND: Capecitabine-induced hand-foot syndrome (HFS) is a common condition that significantly affects patients' quality of life. The exact underlying mechanisms are currently not clearly understood. Therefore, the study of predictive factors for HFS is of critical importance. MATERIALS AND METHODS: This prognostic factor research used a retrospective observational cohort as the study design. Data collected from the medical records of 205 patients treated with capecitabine between January 2019 and June 2022 were subjected to univariable and multivariable regression analysis to determine the predictive factors for the development of grade 2 and grade 3 HFS. RESULTS: The incidence of grade 2 and grade 3 HFS was 26.8%. The independent predictive factors, such as age over 60 years (OR 4.80, 95% CI: 2.16-10.68, <0.001), capecitabine dose greater than 3000 mg/day (OR 2.47, 95% CI: 1.09-5.59, =0.030), and the number of cycles five or more in the total capecitabine regimen (OR 2.94, 95% CI: 1.29-6.71, =0.01), were significantly associated with the development of grade 2 and grade 3 HFS. CONCLUSIONS: Independent predictive factors for the development of grade 2 and grade 3 HFS in patients treated with capecitabine include age over 60, capecitabine dose greater than 3000 mg/day, and patients who plan to undergo five or more cycles in the total capecitabine regimen. This knowledge can be valuable for guiding clinical monitoring and follow-up of patients.