Interleukin-6 (IL-6) has an important role in the pathogenesis of chronic viral hepatitis and related liver diseases. Although host genetics associated with the response to anti-viral treatment have been reported, little is known about the relationship between IL6 genetic polymorphisms and the outcome of hepatitis B virus (HBV) infection. In this study, we determined the genotype distribution of rs1800796 polymorphism in healthy controls and cases including chronic HBV (CHB), hepatitis C virus and HIV infection. The rs1800796 was found to be associated with clinical outcome of CHB in experimental and validation cohort. The rs1800796C allele has twofold higher promoter activity than G allele. Consistently, CD14+ monocytes from subjects carrying the rs1800796C allele produced more IL-6 in response to in vitro HBV core antigen stimulation than those carrying G allele. Moreover, CHB patients carrying rs1800796C allele have significantly higher T-helper 17 (Th17) and regulatory T cell (Treg) ratio. Finally, a transcription factor C/EBPα binds in higher affinity to rs1800796C allele than to G allele. These results suggest that genetic predisposition to higher IL-6 production is associated with increased risk to HBV infection and hepatic inflammation, which might be due to C/EBPα-mediated regulatory effect on Th17 and Treg responses. Appropriate manipulation of IL-6 expression might be used to prevent and treat HBV infection.