Background: The CIITA plays a pivotal role in immune response by controlling HLA class II gene expression, and NTCP is a functional receptor for HBV. These variants may affect outcomes of HBV infection. Objectives: The aim of this study was to determine the association of CIITA and NTCP gene variants with chronic HBV infection and disease progression. Methods: Based on serological and clinical characteristics, 671 unrelated Han Chinese individuals were divided into three major groups: healthy subjects (170 cases), clearance subjects (199 cases), and subjects with chronic HBV infection (305 cases) consisted of 169 chronic hepatitis B, 68 liver cirrhosis, and 68 hepatocellular carcinoma patients. By logistic regression analysis, the rs2296651 AG + AA genotype decreased significantly in the chronic HBV infection group when compared to healthy subjects in dominant genetic models (OR = 0.41, 95%CI: 0.23 -0.74). The rs9302456 CT + TT genotype and rs12882299 CT + CC significantly increased the risk of chronic HBV infection when compared to healthy subjects in dominant genetic models (rs9302456: OR = 2.24, 95%CI: 1.17 -4.29; rs12882299: OR = 1.97, 95%CI: 1.27 -3.07). Using the chronic hepatitis B patients as control group, our study showed that there was no association between CIITA and NTCP gene variants and HBV progression. Conclusions: Our study suggested that genetic variations in CIITA and NTCP were significantly associated with chronic HBV infection in Han Chinese populations, but not with HBV progression.