To assess whether urea-based cream (UBC) has prophylactic benefits on sorafenib-induced hand-foot skin reaction (HFSR) in patients with advanced hepatocellular carcinoma (HCC). In this randomized, open-label trial, 871 patients with advanced HCC throughout China were treated with 10% UBC three times per day plus best supportive care (BSC; n = 439) or BSC alone excluding all creams (n = 432), starting on day 1 of sorafenib treatment, for up to 12 weeks. HFSR was assessed every 2 weeks and at 14 weeks for patients completing the study. Once HFSR occurred, patients were allowed any cream, including a UBC. The 12-week incidence of any grade HFSR was significantly lower in the UBC group versus the BSC-alone group (56.0% v 73.6%, respectively; odds ratio [OR], 0.457; 95% CI, 0.344 to 0.608; P < .001), as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004). Median time to first occurrence of HFSR was significantly longer in the UBC group than the BSC-alone group (84 v 34 days, respectively; hazard ratio, 0.658; 95% CI, 0.541 to 0.799; P < .001). Elevated AST was associated with increased risk of HFSR but did not alter the treatment effect of UBC. UBC plus BSC, compared with BSC alone, did not affect the sorafenib dose reduction or interruption rate (9.1% v 11.8%, respectively; P = .1937), response rate (11.1% v 10.1%, respectively; P = .6674), or disease control rate (98.8% v 98.2%, respectively; P = .5350) at week 12. UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC. Blinded, randomized, placebo-controlled trials to determine the role of UBC on the incidence and severity of HFSR are warranted.