Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in patients with cirrhosis in the U.S. HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy and overall survival in patients with cirrhosis. However, current surveillance strategies suffer from poor adherence and suboptimal sensitivity. The multi-analyte HelioLiver test is a novel blood test for the early detection of HCC. The test provides a qualitative result based on a multiparametric algorithm that incorporates information from cell-free DNA (cfDNA) methylation markers, protein tumor markers (AFP, AFP-L3%, DCP) and patient demographic characteristics (sex, and age). Here, we describe the protocol for a prospective, multicenter clinical trial designed to investigate the performance of this multi-analyte blood test in cirrhosis patients at risk for HCC. Methods: The Prospective Clinical Trial to Detect Liver Cancer through Quantification of cfDNA Methylation in Blood Samples (CLiMB) is a longitudinal, multicenter, prospective study with a targeted enrollment of 1,600 participants. The main inclusion and exclusion criteria are described in the table. Within the Initial Surveillance Visit (t=0 months), all enrolled subjects will provide blood specimens for the multi-analyte blood test and undergo conventional ultrasound to examine the liver. Every subject will then undergo diagnostic imaging by multiphasic MRI to determine the clinical truth. The results of diagnostic imaging will be scored by a Liver Reporting and Data System (LI-RADS) score and the number and size of any malignant lesions identified will be recorded. After the Initial Surveillance Visit (t=0 months), subjects with an indeterminant HCC finding by MRI (LI-RADS 3) will be recommended to have up to three Follow-Up Visits (t=6 months, t=12 months, and t=18 months) to attempt to resolve the clinical truth for these subjects. The primary endpoints of the trial are to demonstrate the superiority for sensitivity and non-inferiority for specificity of the multi-analyte blood test over ultrasound for the detection of HCC. The data of all diagnostic imaging by MRI will be saved and uploaded for evaluation by a blinded, centralized team of radiologists, which will be used as the basis of the clinical truth for all subjects. All participants are currently enrolled across the U.S. from over 40 clinical sites. Clinical trial information: NCT03694600.