Background: S-CUBE was a randomized, double-blind, phase III trial evaluating the efficacy and safety of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (HCC). The study’s primary outcome was presented at the 2015 ASCO Annual Meeting. Although S-1 did not significantly improve overall survival (OS) in all cohort (hazard ratio [HR] = 0.86; confidence interval [CI] = 0.67–1.10; P = 0.2201), we conducted predictive enrichment strategy analysis (PESA) to identify a patient population with a better response to S-1. Methods: Predictive enrichment strategy is a newly introduced concept proposed by the United States Food and Drug Administration, “to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population. (Temple R. [2012] )” Therefore, in our study, PESA provides robust results and identifies advanced HCC patients who are more likely to respond to S-1. Clinically meaningful baseline characteristics were selected to create a scoring system; patients were ranked based on their scores, and the population with a better response was identified. Patient mapping was used to further characterize the population. Results: The full S-CUBE analysis set consisted of 333 patients, including 222 in the S-1 arm and 111 in the placebo. PESA and patient mapping identified 219 patients (65.8% of the total population) as the high-response patient population. High-response patients are classified as those with the following criteria; 1) TNM stage III, IVa, or IVb, 2) Child-Pugh class A, and 3) Levels of both the tumor markers are not high (AFP ≥ 400 ng/mL and PIVKA-II ≥ 10000 mAU/mL). In this population, the median OS of S-1 group was significantly longer than that of placebo group (426.0 days vs. 375.5 days; HR, 0.69; 95% CI, 0.51 to 0.93; P = 0.0156). Conclusions: PESA and patient mapping identified a high-response patient population to S-1. This statistically robust analysis demonstrated S-1 showed survival benefit for identified clinically-important population of sorafenib-refractory advanced HCC patients. Clinical trial information: JapicCTI-090920.