Chronic hepatitis B is a dynamic process and its natural history can be summarized in five phases, but these are not necessarily consecutive. (1) The “immune tolerance phase” is characterized by HBeAg positivity, high levels of HBV replication (as reflected by serum HBV DNA), normal or low levels of transaminases, mild or no liver necroinflammation, and no or only slow liver fibrosis. At this stage, the chances of spontaneous negative HBeAg regression are low. This phase is more common and somewhat longer in individuals infected in the perinatal period or early in life. These patients are highly infectious due to high viral levels. (2) The immune active phase is characterized by HBeAg positivity, low levels of viral replication (as evidenced by low levels of serum HBV DNA), elevated or fluctuating transaminase levels, moderate to severe hepatic necroinflammatory activity, and more rapidly progressive liver fibrosis than in the previous phase, which can last from weeks to years. This period can occur several years after the immune tolerance period and mostly occurs after the infected individual enters adulthood. (3) “Inactive HBV carrier state” occurs after the transition from HBeAg to anti-HBe and is characterized by very low or undetectable serum HBV DNA levels and normal transaminases. The risk of cirrhosis and HCC is low in the vast majority of patients. In cases of undetectable HBV DNA lasting several years, spontaneous HBsAg negativity or serologic conversion to HBsAb can occur, with an incidence of 1-3%. (4) HBeAg-negative CHB occurs after HBeAg serologic conversion during the immune active phase and represents the later stage of the natural history of CHB. It is characterized by periodic reactivation, fluctuating HBV DNA and transaminase levels and hepatitis activity. Such patients are HBeAg negative, have HBV mutations due to nucleotide substitutions in the promoter region of the pre-C/C region, and fail to express or express only low levels of HBeAg. HBeAg-negative CHB has a low probability of long-lasting spontaneous remission. It is important, but sometimes difficult, to differentiate between patients with true inactive HBV carriers, who have a good prognosis and a low risk of complications, and patients with HBeAg-negative CHB in spontaneous remission, who have active liver disease and a higher risk of progressive liver fibrosis, cirrhosis and its associated complications (e.g., decompensated cirrhosis and HCC). Detailed evaluation of the patient is essential, with ALT and HBV DNA levels checked every 3 months and at least 1 year of follow-up, allowing observation of fluctuating activity in active HBeAg-negative CHB. (5) HBV DNA can be detected in the liver during the HBsAg-negative phase after the disappearance of HBsAg, suggesting the persistence of low levels of HBV replication. Generally, HBVDNA is undetectable in the serum and anti-HBc with or without anti-HBs can be detected. disappearance of HBsAg is associated with improved prognostic outcome and reduced risk of cirrhosis, hepatic decompensation and HCC.