Background: Hand-foot skin reaction (HFS) is a well-known adverse event that affects the quality of life in patients (pts) who receive multichines inhibitors (TKIs). To prevent HFS, prophylactic depressurization is considered to be one of the important strategies. However, the evidence of depressurization as a prophylactic use for HFS is limited. Therefore, we conducted a phase 3 trial to evaluate the efficacy of depressurization using hydrocolloid dressing, which was usually used for wounds such as decubitus ulcers. Methods: This is a phase 3 randomized self-controlled study to evaluate the efficacy of hydrocolloid dressing by comparing whether or not to add hydrocolloid dressing to prophylactic moisturizing for HFS. The eligible pts were to have unresectable colorectal cancer (CRC), gastrointestinal tumor (GIST), or hepatocellular carcinoma (HCC) and planned to receive either regorafenib or sorafenib. From the start of regorafenib or sorafenib, standard supportive care with moisturizing care alone was performed on one sole of the foot. Moisturizing care plus hydrocolloid dressing was applied to the other side soles of the foot. The primary endpoint was an incidence of grade 2 or more severe HFS (soles of the feet only) assessed by NCI CTCAE v.4.0. Grading of HFS was done according to pre-determined criteria, which consists of blinded central review of photographs of the foot, pain intensity (numerical rating scale) and interference score assessed by pts. The ethical approval was obtained from National Cancer Center Hospital. This study was registered with UMIN Clinical Trial Registry (UMIN000034853). Results: Between Jan 2019 and May 2021, 50 pts were enrolled. The median age was 62.5 years old, and cancer types were CRC in 78%, GIST in 12%, and HCC in 10% of the patients. 48 pts received regorafenib, and 2 pts received sorafenib. The table shows the summary of HFS in each arm. The primary endpoint of the incidence of grade 2 or more severe HFS was significantly lower in the hydrocolloid dressing arm than in the control arm (20% vs. 50%, p < 0.0001). Time to grade 2 or more severe HFS was significantly longer in the hydrocolloid dressing arm (hazard ratio 0.32, p = 0.0017). The incidence of moderate, severe, or very severe in patient-reported HFS using PRO-CTCAE was also lower in the hydrocolloid dressing arm (10% vs. 32%, p = 0.0002). Conclusions: Our study showed the efficacy of the prophylactic use of hydrocolloid dressing for HFS induced by multitargeted kinase inhibitors. Prophylactic moisturizing plus depressurization is the standard of care for this population. Multidisciplinary care plays an important role in the success of treatment with TKIs. Clinical trial information: UMIN000034853.