Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is an intermediate replicative episome which is stable and not easy to eliminate. cccDNA serves as the template for HBV replication and plays an important role in persistence of HBV infection in hepatocytes, and it is also a biomarker of HBV activity. Studies suggested that HBV has extrahepatic infectivity and cccDNA could be detected in peripheral blood mononuclear cells (PBMC). The predictive values of HBV cccDNA in PBMC for HBV recurrence after liver transplantation and antiviral therapy and mother-to-child transmission of HBV in patients with hepatitis B, as well as the possible mechanism of cccDNA involved in extrahepatic HBV infection, are summarized. Therefore, the detection of HBV cccDNA is of great significance for the study and treatment of HBV.