The host genetic compound plays a vital role in determining clinical outcomes of hepatitis B virus (HBV) infection. The tumor necrosis factor receptor-associated factor family member-associated nuclear factor-alpha B (NF-kappa B) activator (TANK) takes part in the tumor necrosis factor-alpha (TNF-alpha)-mediated NF-kappa B signaling pathway and the interferon (IFN)-induction pathways that have relevance to HBV-related liver disease. In this report, we explored whether the intronic polymorphism rs3820998 of the TANK gene was associated with outcomes of HBV infection by binary logistic regression analysis. A total of 1305 unrelated Han Chinese patients recruited from Wuhan, including 180 acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients, 331 HBV-related liver cirrhosis (LC) patients, 308 HBV-related hepatocellular carcinoma (HCC) patients, and 486 asymptomatic HBV carriers (AsC) were genotyped using the Taq Man probe method. Logistic analysis revealed that the single-nucleotide polymorphism (SNP) rs3820998 was significantly associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p = 0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p = 0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p = 0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p = 0.034). These results indicate that the G > T variant is a protective factor in the development of ACLF-HBV and LC, and that the SNP rs3820998 in the TANK gene may play a role in mediating susceptibility to ACLF-HBV and LC in a Chinese Han population.