Multivariate analyses revealed that M2P-HCC was an independent predictor of increased risk of HCC (OR = 1.16 [1.09-1.22], <i>p</i> < 0.001).<h4>Conclusions</h4>M2P-HCC liquid biopsy demonstrated good performance for early liver cancer screening in high-risk populations of Hepatitis B-related liver cancer, exhibiting better sensitivity than the combination of AFP and US. This evidence concerns the gene AFP and liver cancer.