BackgroundNew biomarkers are needed to detect hepatocellular carcinoma at an earlier stage and to individualize treatment strategies. IL-6 has been proven to be associated with liver cancer in numerous studies.AimTo evaluate the value of the IL-6 promoter methylation level as a noninvasive biomarker for the diagnosis of liver cancer.MethodsA retrospective analysis of 165 patients with HBV-associated hepatocellular carcinoma (HCC), 198 patients with chronic hepatitis B (CHB) and 31 healthy controls were involved. The methylight was detected the methylation level of the IL-6 promoter in peripheral blood mononuclear cells (PBMCs), clinical and laboratory parameters were obtained.ResultsIL-6 promoter methylation levels were significantly lower in patients with HCC (median 53.59%, interquartile range 52.01–54.75%) than in those with CHB (median 56.05%, interquartile range 54.65–57.67%; Pvs. 0.686, P=0.027], And the combined use of AFP and IL-6 methylation level can improve the area under the receiver operating characteristic curve (p=0.011).ConclusionIL-6 promoter hypomethylation is present in hepatocellular carcinoma, and it may be used as a noninvasive biomarker to detect early liver cancer.