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Introduction Hand-foot syndrome (HFS) is a dermatological side effect of chemotherapies such as capecitabine and pegylated liposomal doxorubicin. Over recent years, numerous randomised controlled trials (RCTs) have investigated various pharmacological strategies to prevent HFS. Although urea cream and celecoxib have shown promising results, the efficacy of topical diclofenac remains unclear. To provide a comprehensive comparison of pharmacological interventions for HFS prevention in cancer patients undergoing chemotherapy, we conducted a network meta-analysis (NMA).Methods We systematically searched PubMed, Cochrane and Scopus for relevant RCTs published up to November 2024. The primary outcome was the incidence of moderate to severe HFS (grade 2–3), while secondary outcomes included the occurrence of all-grade HFS (grade≥1) and chemotherapy modifications. Risk ratios (RR) with 95% CIs were estimated for all outcomes using NMA.Results Thirteen RCTs comprising 1983 patients, most of whom received capecitabine (n=1849) were included, evaluating five pharmacological interventions. Both topical diclofenac (RR 0.26, 95% CI 0.10 to 0.66) and celecoxib (RR 0.46, 95% CI 0.26 to 0.84) significantly reduced the risk of moderate to severe HFS compared with placebo. Notably, topical diclofenac was the only intervention that significantly reduced the incidence of all-grade HFS and the need for chemotherapy modifications.Conclusion Our NMA demonstrates that topical diclofenac provides the most robust protective effect among available pharmacological interventions for HFS prevention and is also associated with fewer chemotherapy modifications. These findings support its consideration as a preferred preventative strategy for patients at risk of HFS during chemotherapy.PROSPERO registration number CRD42025643635