Background: The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear. Aim: To assess whether genetic polymorphisms influencing the susceptibility to develop HCC are also associated with HCC prognosis. Methods: We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all-cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment. Results: The final sample included 439 patients; 74% had either non-alcoholic fatty liver disease or alcohol-related liver disease. There were 321 deaths during a mean follow-up of 1.9 years per participant. Kaplan–Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively. In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all-cause mortality risk (aHR: 0.74; 95% CI: 0.61–0.90; p = 0.003). Other associated factors were Baveno stage 3–4 (aHR: 1.65; 95% CI: 1.05–2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17–0.37; p < 0.001). Conclusions: The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC.