The concept of occult infection caused by hepatitis B virus (HBV) is determined as the presence of HBV DNA in blood sera or liver with the absence of detectable HBsAg. The actuality of this problem is associated with the fact, that occult hepatitis B (OHB) can be transmitted during hemotransfusions, cause reactivation of chronic hepatitis B in immune compromised individuals, facilitate development of liver cirrhosis and hepatocellular carcinoma. Several different hypotheses of OHB immunopathogenesis have been proposed, including a low number of copies of HBV DNA, altered immune response of the macroorganism, genetic variability of the S gene, integration of viral DNA into host genome, infection of mononuclear cells of peripheral blood, presence of immune complexes that hide HBsAg, and interference by other viruses such as HCV and HIV. Molecular mechanisms of HBV virus in HBsAg-negative individuals are not fully understood, however, viral mutations seem a very significant factor. Approaches of OHB prophylaxis including use of a polyvalent vaccine, that allows vaccination against wild and mutant HBV viruses, are examined.