Abstract Understanding the genetic and immune heterogeneity in hepatocellular carcinoma (HCC) is crucial as treatments advance towards personalisation. This study characterises the genetic and immune heterogeneity within a population of 56 tumours from 28 patients, 10 of whom have multifocal disease, obtained from patients undergoing surgery at the Leeds Teaching Hospital NHS Trust. These samples represent the most common aetiological groups found in the UK: alcohol-related liver disease, non-alcoholic fatty liver disease and hepatitis C. Whole exome sequencing was performed on DNA from these tumour alongside matched background liver samples to determine tumour-specific variants. Tissue sections were stained for both proliferation and immune cell markers. Tumours across aetiological groups showed significant levels of variation, with high inter-individual variation. Analyses of multifocal tumours revealed significant discordance in genetic and immune cell profiles, both between multi-centric primary and metastatic tumours. This work emphasises the genetic and immuneheterogeneity in HCC across HCC subtypes, between and within individuals, highlighting mechansisms for therapeutic resistance and the need for personalised medicine.