Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; = 54), sorafenib (group B; = 82) or TACE (group C; = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3-9.7), 4.1 months (95% CI: 3.6-4.7) and 5.0 months (95% CI: 2.9-7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0-18.1), 8.4 months (95% CI: 6.0-10.8) and 10.5 months (95% CI: 7.5-13.6), respectively (group A vs. group B: < 0.001; group A vs. group C: = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.