AIM To assess the impact of underlying liver disease etiology on the presenting features and outcomes in a large cohort of patients with hepatocellular carcinoma (HCC). METHODS A prospective database of all patients with HCC was established from 1998 to March 2012. One thousand and seventy-eight patients were categorized into three groups, based on the etiology of their liver disease: hepatitis B virus (HBV), hepatitis C virus (HCV) and non-viral liver disease (NVLD). Overall survival was determined by Kaplan Meier analysis to time of death or last follow-up. RESULTS HCC patients with HCV (85%) were more likely to be diagnosed as part of a surveillance program, compared to HBV or NVLD (both 71%) (p < 0.001). Patients with NVLD were more likely to receive best supportive care (29%) compared to those with HBV (21%) or HCV (20%) (p < 0.02). Twelve percent of NVLD and 13% of HBV patients underwent liver transplantation compared to 21% of HCV patients (p = 0.001). Median survival from presentation was lowest in NVLD (1.7 years) when compared to HBV (2.8 years) and HCV (2.6 years) (p < 0.05). In multivariate analysis, independent predictors of survival included Child Turcotte Pugh score, size of dominant lesion, absence of vascular invasion, and management with surgical resection or liver transplantation. Patient age and the etiology of the underlying liver disease were not independent predictors of survival CONCLUSION Patients with NVLD and HCC were less likely to be enrolled in a HCC surveillance program and are less likely to have curative therapies such as liver resection and transplantation after diagnosis with HCC, when compared to patients with Hepatitis B and Hepatitis C.