<p>Early-stage diagnosis of Hepatocellular Carcinoma (HCC) vastly improves outcomes for patients. However, most patients are diagnosed late-stage when their only option is palliative treatment. In this study we propose a risk stratification method that combines cutoffs for PAGE-B with cutoffs for a prototype serological immunoassay, LG2m, as well as 2 conformité européenne (CE)-certified serological immunoassays in AFP and PIVKA-II run on the high-throughput ARCHITECT (Abbott Laboratories, North Chicago, IL) instrument. In this study, immunoassays for LG2m, PIVKA-II, and AFP were used to test serial plasma from 1329 Asian chronic hepatitis B (CHB) patients at baseline, year 1, year 3, and year 5. These CHB patients were put on first-line nucleos(t)ide analogue (NA) therapy and monitored for hepatocellular carcinoma (HCC) every 6–9 months. A Kaplan-Meier analysis was performed incorporating cutoffs for LG2m, PIVKA-II, AFP and PAGE-B from plasma collected after 1 year of NUC initiation. Combined cutoffs for these factors detected 92.9% of patients diagnosed with HCC within 6 years. Relative risk analyses incorporating these same cutoffs, determining HCC diagnosis within 2 years, had sensitivities of 94.7%, 84.6%, and 84.6% when run on plasma taken at Year 1, Year 3, and Year 5 respectively. The high sensitivity of these models, and the fact that their Kaplan-Meier and relative risk analyses remained statistically significant, demonstrates the strength and consistency of a risk-stratification model that incorporates the prototype LG2m assay with known factors such as PIVKA-II, AFP, and PAGE-B, when risk stratifying for HCC within a cohort of Asian CHB patients on NA therapy. With more effective risk-stratification more patients can be given the option of curative treatments over palliative treatments.</p>