Background: An unmet medical need persists for patients (pts) with sorafenib-refractory advanced hepatocellular carcinoma (HCC). This study was conducted to evaluate the efficacy and safety of S-1 in pts with sorafenib-refractory advanced HCC. Methods: Japanese men and women (aged ≥ 20 years) with Child-Pugh (C-P) A or B liver function and disease progression with or intolerance to sorafenib were randomized in a 2:1 ratio. S-1 (80, 100, or 120 mg/day) or a placebo was administered orally, according to the body surface area on days 1–28 of a 42-day cycle until disease progression or unacceptable toxicities were observed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. For a statistical consideration of the heterogeneous population with advanced HCC, we conducted the subgroup analysis. Results: A total of 334 pts were enrolled (S-1 = 223, placebo = 111). Patient characteristics were well balanced; median age, 70.0 years; C-P A liver function, 81.0%; vascular invasion, 17.7%; and extrahepatic metastasis, 53.8%. The median OS was 337.5 days with S-1 and 340.0 days with the placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.67–1.10; P = 0.220). The median PFS were 80 and 42 days, respectively (HR, 0.60; 95% CI, 0.46–0.77; P < 0.001). ORRs were 5.4% and 0.9%, respectively (P = 0.068). In the subgroup analysis showed the efficacy of S-1 on OS was different depending on patient characteristics; C-P liver function, HR was 0.79 (C-P A) and 1.19 (C-P B); Tumor stage, HR was 2.08 (Stage I/II) and 0.79 (Stage III/IV). The main adverse events (AEs) with S-1 were anorexia, fatigue, elevated total bilirubin, and diarrhea. Most AEs were mild to moderate, and the study discontinuation rate due to AEs was 19.2% in S-1 pts. Conclusions: Although S-1 did not statistically extend OS compared to the placebo in pts with sorafenib-refractory advanced HCC, the subgroup analysis showed S-1 has potential to improve OS in the clinically-important population. The observed benefit in the outcomes of PFS and subgroup analysis warrant further investigation. Clinical trial information: JapicCTI-090920.