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Background and objectives Treatment of hepatocellular carcinoma (HCC) >5 cm is problematic, as patients are often outside transplantation criteria, and cirrhosis compromises curative resection. The purpose of this study was to evaluate survival following treatment with ablation compared to chemotherapy in large HCC. Methods This was a retrospective cohort study of the National Cancer Database (NCDB) Participant User File from 2004 to 2017. Patients with HCC >5 cm in diameter treated with ablation versus chemotherapy alone were compared. Inverse probability-weighted propensity scores were used to model treatment assignments in the Cox proportional hazards model. Results A total of 14,783 HCC patients with tumors >5 cm and <9 cm were treated with chemotherapy (N=14,127) or ablation (n=656). After adjustment for stage, comorbidity, insurance status, facility type, and race, survival was significantly improved with ablation. The treatment effect of ablation was estimated using inverse-probability-weighted propensity scores, and the survival advantage was 19 months longer (p<0.001; 95% CI: 10.1-28.2) compared to chemotherapy. Conclusions Despite the reluctance to use ablation in lesions >5 cm, our analysis suggests a survival advantage when compared to chemotherapy. These results are promising, and future trials should evaluate ablation in combination with other local and systemic therapies.