Background: Capecitabine induced HFS is associated with deterioration of quality of life of patients and dose of capecitabine is often reduced to manage this adverse event. Celecoxib is the only effective intervention in preventing HFS; however, its widespread use is limited due to its own safety concerns. We conducted this study to assess the efficacy of topical diclofenac in preventing capecitabine induced HFS. Methods: Patients with breast and gastrointestinal (GI) cancers, planned for capecitabine (monotherapy or combination) treatment were randomized in 1:1 to receive topical diclofenac or placebo gel for 4 cycles or until development of HFS, whichever was earlier. Stratified (male or female; capecitabine monotherapy or combination therapy) permuted variable size block randomization was done using a computer-generated random numbers sequence. Primary objective was to compare the incidence of grade 2 or higher HFS in diclofenac and placebo arms. Secondary objectives were incidence of any grade HFS, capecitabine dose changes due to HFS and self-reported adherence with application. Results: A total of 263 patients were randomized to apply topical diclofenac gel (n=130) or placebo (n=133). Baseline characteristics were similar in both the arms (Table). The incidence of grade 2 or higher HFS was 3.8% (95% CI, 1.6%-8.9%) in the diclofenac arm compared with 15.0% (95% CI, 9.9%-22.2%) in the placebo arm (P=0.003). Any grade HFS was significantly lower in the study arm compared with the placebo arm (6.1% vs 18.1%; P=0.003). A lower incidence of HFS was observed in the diclofenac arm across the subgroups (breast and GI cancers; males and females). Capecitabine dose reductions were less frequent in the diclofenac arm (3.8%) compared with the placebo arm (15%) (P=0.002). Adherence to topical treatment was similar in the diclofenac arm (96.7 +/- 19.1%) compared with the placebo arm (94.0 +/- 28.3%) (P=0.36). Other capecitabine associated adverse events, including diarrhea, mucositis, and myelosuppression were not significantly different in both the arms. Conclusions: Topical diclofenac is effective in preventing all grades of HFS in patients receiving capecitabine. Diclofenac application was also associated with lesser dose reductions of capecitabine. This trial establishes topical diclofenac as the new standard of care to prevent capecitabine associated HFS. Clinical trial information: CTRI/2021/01/030592.