Background: Hepatitis B virus (HBV) is a global health hazard, which may cause acutehepatitis, fulminant hepatic failure, chronic hepatitis, liver cirrhosis, and even hepatocellular carcinoma. There are 350 million chronic HBV infected patients in the world, and annually 1 million patients died of complication associated with HBV. During the chronic course of HBV infection, HBeAg seroconversion generally indicates the decrease in viral replication and subsidence of disease activity. However, the role of host factors on the process of spontaneous HBeAg seroconversion is unclear. Thus, we aimed to elucidate the possible roles of hormone and cytokine on the complex immune process. Study Design and Methods: This is a long-term prospective cohort study. To confirm the impacts of hormone, we investigated the serum testosterone levels and HBV viral load at early (10years), middle (15 years), and late (20years) puberty. We also checked the SRD5A2 V89L polymorphism and the CAG repeat number of androgen receptor exon-1. About the roles of cytokines, we checked 11 single nucleotide polymorphism located at 5 Th1 and Th2 cytokine gene (IL-2, IL-4, IL-10, IL-12β, IFN-γ), and the serum cytokine levels and viral load at immune tolerance phase, inflammatory/clearance phase, and post HBeAg-seroconversion inactive phase. We further investigated the association between IL-10 and IL-12 in the liver with HBV infection and the relationship with IFN-γ and possible downstream signals. The impact of different host immune stress (IL-10 genotype) on the mutation pattern of HBV precore/core gene was also done. Results: Earlier onset of puberty and higher SRD5A2 enzyme activity were associated with more viral load decrement during the puberty period (10-20 years) and earlier spontaneous HBeAg seroconversion. IL-10 -1082 G/G genotype and IL-12β C/G genotype were associated with higher baseline IL-10 serum levels and HBcAg inducible IL-12 levels, and both predict earlier onset of spontaneous HBeAg seroconversion. Intrahepatic IL-10 and IL-12βmRNA levels were associated with IFN-γ expression, which associated with lower furin and higher PD-1/PD-L1 expression in subjects with chronic HBV infection at the inflammatory phase. G/G genotype of IL-10 -1082 also associated with higher C2189A mutation rate at the HBV precore/core gene, which is also associated with lower HBV viral load. Discussion: This study provided some new evidence of the impacts of hormone and cytokine on the natural course of chronic HBV infection. We also demonstrated that, different host immune stress may associate with different HBV mutation pattern and clinical outcomes.