The template of hepatitis B virus transcription, the covalently closed circular DNA (cccDNA), plays a key role in the life cycle of the virus and permits the persistence of infection. It has been suggested that hepatitis B surface antigen (HBsAg) quantification reflects the concentration of cccDNA in the liver. In hepatitis B e antigen (HBeAg) positive chronic hepatitis B, HBsAg levels are higherduring the immune tolerance phase than during the immune clearance phase. During the natural history of chronic hepatitis B, serum HBsAg declines progressively from the immune-tolerant to the low replicative phase. In HBeAg negative patients, the combination of low hepatitis B virus (HBV) DNA (<2000 IU/ml) and low HBsAg levels (<1000 IU/ml) can predict inactive carrier status, low risk of hepatocellular carcinoma, and the probability of HBsAg loss. HBsAg in combination with HBV DNA predicts the outcome of Peg-Interferon therapy: An absence of decline at week 12 is a good predictor of non-response and to stop therapy. Any decline at week 24, suggests that therapy should be continued to 48 weeks. Although the decrease in HBsAg decline slow with nucleos(t)ide analogue therapy, a rapid decline can predict future HBsAg seroclearance. A level <100 IU/ml during six consecutive months could be a marker of a sustained response after treatment cessation.