The appearance of replication-competent variants of HBV with mutations in the envelope and precore/core and X proteins emphasizes that these proteins are the focus of immune selection pressures in the human host. The presence of an antibody response in the absence of a CTL response may create the ideal selection environment. This occurs in the early phase of passive/active immunization against HBV envelope proteins in neonates born to HBV-infected mothers and also during the emergence of HBeAg-negative variants during and after HBe antigen/antibody seroconversion in chronic HBV carriers with defective CTL responses. The sequence and speed of application of the multiple selection pressures (humoral and possibly cellular) determine the virologic and clinical outcome. When these variant viruses are passed to a new host, in the absence of the immune selection pressures or modified immune pressures that resulted in their selection, a picture clinically different from that seen in the original host may emerge.