AbstractBackground and AimThe rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic‐associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population.MethodMulticenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2‐year period.ResultsThree hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the “mixed” group), and non‐MAFLD (n = 179) were included in the study. Alcohol‐associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD‐HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self‐reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate.ConclusionEqual to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.