BACKGROUND: Hand-foot syndrome (HFS) is a common adverse event of capecitabine causing treatment modifications. Topical urea cream can reduce sorafenib-induced hand-foot skin reaction. However, its benefit in preventing capecitabine-associated HFS was not seen early in the course and had been unknown with long-term use. The aim of this study was to evaluate the efficacy of urea cream for HFS prophylaxis throughout capecitabine treatment. METHODS: Patients with cancer who received capecitabine were randomized (1:1) to receive usual care alone or in combination with urea-based cream. The incidence and degree of HFS were assessed at each capecitabine cycle. The primary endpoint was the proportion of patients with any grade HFS. The secondary endpoints included the proportion of patients with severe (≥ grade 3) HFS, modifications in capecitabine because of HFS, and HFS onset. RESULTS: After a median of six capecitabine cycles, any grade HFS was reported by 68 of 109 patients (62.4%) who received usual care and by 60 of 107 patients (56%) who used urea cream (p = 0.36). The patients who received usual care and urea cream had similar proportions of grade 3 HFS occurrence [52 (47.7%) vs. 44 (41.1%), respectively, p = 0.34] and needed capecitabine modification because of HFS [20 patients (18.3%) vs. 17 patients (15.9%), respectively, p = 0.89], as well as similar HFS onset. CONCLUSIONS: Urea-based cream did not prevent capecitabine-associated HFS, reduce capecitabine modification, and delay HFS onset. However, it had a tendency to lessen HFS severity, especially in the later cycles of capecitabine. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT05348278, registered on April 21, 2022.