Abstract: Objective To investigate the clinical features of HBsAg-negative HBV-related hepatocellular carcinoma (HCC) .Methods The patients who were newly diagnosed with HCC from January 2005 to January 2012 were enrolled.According to the HBV-related serological markers, the patients were divided into HBsAg-negative HBV-related HCC group and hepatitis B-related HCC group.A retrospective analysis was performed for the clinical and laboratory examination data at initial diagnosis, including sex, age, hepatitis B virus markers, total bilirubin (TBil) , albumin (Alb) , alpha-fetoprotein (AFP) , HBV DNA, body mass index (BMI) , drinking history, history of diabetes, therapies, and follow-up results.The t-test was used for comparison of normally distributed continuous data between groups;the non-normally distributed data were expressed as median and interquartile range (Q1 and Q3) , and the Wilcoxon rank sum test was used for comparison of non-normally distributed continuous data between groups;the chi-square test or Fisher's exact test were used for comparison of categorical data.The log-rank test was used to compare survival curves between the two groups, and the Kaplan-Meier method was used to calculate survival rates.Results Compared with the hepatitis B group and all patients, the HBsAg-negative group had a significantly higher mean age (59.42 ± 11.13 years) and significantly higher proportions of patients with age > 60 years (46.85%) , low body weight (12.24%) , and overweight (20.98%) (all P < 0.01) .Compared with all patients and the hepatitis B group, the HBsAg-negative group had a significantly lower male-to-female ratio (2.86:1) , a significantly lower proportion of patients regularly undergoing physical examination every year (10.41%) , a significantly lower HBV DNA positive rate (1.77%) , and significantly lower proportions of patients with smoking and drinking histories (all P <0.01) .Of all patients in the HBsAg-negative group, 64.08%had positive anti-HBs, antiHBe, and anti-HBc, 21.13%had positive anti-HBe and anti-HBc, and 14.79%only had positive anti-HBc.The HBsAg-negative group had a significantly lower AFP level than all patients and the hepatitis B group (P = 0.039) .Compared with the hepatitis B group and all patients, the HBsAg-negative group had a significantly higher proportion of multiple lesions, a significantly greater mean maximum tumor diameter, and a significantly higher number of patients with extrahepatic metastasis (all P < 0.001) .Compared with the hepatitis B group, the HBsAg-negative group had a higher proportion of patients with an Eastern Cooperative Oncology Group Performance Status score of 0 at initial diagnosis (17.69%) and a lower proportion of patients with early-to-medium Barcelona Clinic Liver Cancer stage (stages A and B) (30.26%vs 51.60%, P<0.001) ;the number of patients with stages C and D in the HBsAg-negative group was 1.83 times that in the hepatitis B group (P <0.001) .The HBsAg-negative group had a significantly lower median survival time (15.22 months) than all patients and the hepatitis B group (P = 0.024、0.031) .Compared with all patients and the hepatitis B group, the HBsAg negative group had significantly lower 1-and 3-year survival rates (1-year survival rate:56.0%vs 61.7%and 66.2%, x2=-4.93, P-0.026;3-year survival rate:24.0%vs45.2%and 44.1%, x2= 6.867, P = 0.009) .Conclusion HBsAg-negative HBV-related HCC is commonly seen in patients aged >60 years with positive anti-HBs, anti-HBe, and anti-HBc.The population aged >60 years with HBV infection should be the high-risk population for HCC, and it is recommended to perform HCC screening every 6 months to increase the early diagnostic rate of HBsAg-negative HBV-related HCC.