The natural course of perinatally acquired chronic hepatitis B virus (HBV) infection typically has three chronological phases: (1) immune tolerant phase, (2) immune clearance phase, and (3) inactive or residual phase. However, no obvious initial immune-tolerant phase is evident in adult-acquired chronic infection. HBeAg seroconversion is a hallmark that usually signals the transition from active to inactive HBV infection with ALT normalization and resolution of hepatitis activity. After long sustained remission, spontaneous hepatitis B surface antigen (HBsAg) seroclearance may occur and confers excellent prognosis. On the other hand, HBV may reactivate and trigger immune-mediated liver injuries at an incidence of 2–3% per year, usually in the first 10 years after HBeAg seroconversion. High HBV DNA levels and disease activity are the factors of adverse clinical outcomes such as hepatic decompensation, cirrhosis, HCC, and liver-related mortality. Sustained reduction of HBV replication before the onset of cirrhosis confers a favorable outcome.