Background <p>Hepatocellular carcinoma (HCC) incidence and mortality rates are increasing at a greater pace than any other cancer in Australia. Cirrhosis is the major risk factor for HCC, and early detection of HCC through surveillance of people with cirrhosis can improve outcomes. However, cirrhosis is under-detected in primary care settings, with 60% of patients diagnosed with HCC having unrecognised cirrhosis and not found to be in a surveillance programme. Targeted screening of at-risk populations in primary care using noninvasive tests for liver fibrosis could lead to improved diagnosis of cirrhosis and increased participation in HCC surveillance programmes.</p> Methods <p>This is a prospective multicentre parallel randomised controlled trial of 2470 participants, to evaluate the impact of a cirrhosis detection and hepatocellular carcinoma surveillance pathway compared to usual care in 45–75&#xa0;year olds, with risk factors for chronic liver disease, from regional and urban general practice clinics, across four Australian states. Participants will be randomised 1:1, to usual general practitioner care (control) or a cirrhosis detection pathway (intervention), stratified by clinic and potential hazardous drinking. The cirrhosis detection intervention consists of liver fibrosis blood tests (comprising the Fibrosis-4 Index and Hepascore) and a liver stiffness measurement conducted by FibroScan in those with elevated liver fibrosis blood markers. Participants with elevated FibroScan® values will be recommended for referral for hepatology assessment to determine the need for HCC surveillance. The primary outcome is the between-arm difference in proportion of participants with newly diagnosed cirrhosis in HCC surveillance at 12&#xa0;months. Secondary outcomes at 12&#xa0;months will include the between-arm difference in proportion of participants with a diagnosis of any stage HCC, diagnoses of advanced fibrosis and liver decompensation and mean anxiety state and mean quality of life. The cost-effectiveness of the cirrhosis detection pathway will be determined using data linkage to state and national health datasets. Process evaluation will involve assessment of the optimal cirrhosis detection pathway, along with the barriers and enablers of implementation of this pathway, assessed by participant interviews.</p> Discussion <p>This trial will provide evidence of the efficacy and cost-effectiveness of a cirrhosis detection pathway in Australian general practice settings. This will provide evidence to guide the early identification and appropriate placement of patients in HCC surveillance programmes, resulting in earlier HCC diagnosis and improved outcomes.</p> Trial registration <p>Australian and New Zealand Clinical Trial Registry ACTRN12622000185763p. Registered on 3rd February 2022.</p>