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Background: Hand-foot syndrome (HFS) is a prevalent skin reaction to cytotoxic systemic therapy, mainly Capecitabine. The present study aimed to determine etiologies of HFS in addition to its prevention in colorectal cancer patients with Capecitabine-containing chemotherapy regimen. Method: In this randomized double-blinded study, we recruited 66 eligible patients. The first 33 patients received 25 mg captopril twice daily, while the other 33 were given two placebo tablets. Results: All the patients were assessable for safety and efficacy. Captopril demonstrated a favorable safety profile. The participants in the two groups did not have any significant differences in terms of the median age and the level of hemoglobin (P = 0.45, P = 0.06, respectively). However, the CEA tumor marker was significantly higher in those with HFS (P < 0.05). The incidence of HFS in men and women were 8 (18.6%) and 3 (13%) cases, respectively, and the patients’ sex did not affect the incidence of this syndrome (P = 0.73). Furthermore, according to the stage of colorectal cancer, the difference between the two groups was significant (P < 0.05). Meanwhile, there were no significant differences concerning the grade of colorectal cancer (P = 0.2). Conclusion: The results herein revealed that administration of captopril in colorectal cancer patients with Capecitabine-containing chemotherapy regimen reduced the symptoms and incidence of HFS. On the other hand, CEA tumor marker and the stage of colorectal cancer were in correlation with incidence of HFS.