Objective The progression of liver fibrosis and a male sex are risk factors for hepatocarcinogenesis under nucleos(t)ide analog (NA) therapy. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for hepatocarcinogenesis. This study aimed to investigate the factors involved in hepatocarcinogenesis during NAs therapy, including MAFLD. Methods This study is a retrospective study [observation period: median 9.4 years (2.1-19.6 years)]. The subjects were 164 patients taking NAs for more than 2 years and were hepatitis B envelope antigen (HBeAg)-negative with undetectable hepatitis B virus (HBV)-DNA. The patient had no history of hepatocellular carcinoma (HCC). We investigated the profile of HCC onset after NAs therapy using a decision tree analysis Results HCC developed in 20.7% (34/164) of the patients during the observation period. The prevalence of MAFLD was significantly higher in the HCC group than in the non-HCC group (64.7% vs. 43.9%, p=0.03). In particular, in the low-medium risk group classified by PAGE-B, MAFLD increased the risk of HCC development. According to a multivariate analysis, fibrosis-4 (FIB-4) index≥2.67, a male sex, and MAFLD (OR 2.4, 95%CI 1.0-6.0, p=0.04) were independent factors associated with the onset of HCC. In a decision tree analysis, MAFLD was the second classifier for the onset of HCC, next to the FIB-4 index (MAFLD 62.5%, non-MAFLD 28.5%). Conclusions We found that MAFLD was an independent risk factor for HCC in HBeAg-negative patients with undetectable HBV-DNA after NAs therapy. We further revealed that MAFLD was the second-best classifier for hepatocarcinogenesis, next to the FIB-4 index. MAFLD therefore appears to have a synergistic effect on hepatocarcinogenesis with hepatic fibrosis.