We compared the clinical and serologic features of 118 hepatitis B surface antigen carriers with hepatitis B e antibody (anti-HBe) followed up for 3-10 yr (mean 6.1 yr), separated according to the presence or absence of hepatitis B virus-deoxyribonucleic acid (HBV-DNA) in serum. The test was performed by molecular hybridization. There were 28 carriers with and 90 without viral DNA. Carriers with serum anti-HBe/HBV-DNA had major liver disease; cirrhosis developed during the follow-up period in 9 of the patients. All had the hepatitis B "core" antigen in the liver, localized prevalently in the cytoplasm of the hepatocytes. Among carriers of anti-HBe alone, 73 had persistently normal tests of liver function and 17 had abnormal levels of alanine transaminase and usually minor forms of liver damage at histology. In a group of 24 carriers of hepatitis B e antigen who spontaneously seroconverted to anti-HBe, hepatitis and a prevalent nuclear distribution of intrahepatic hepatitis B core antigen were found in temporal correlation with the presence of hepatitis B e antigen in serum. The replication of the hepatitis B virion terminated and liver disease remitted after seroconversion to anti-HBe. A positive HBV-DNA test in anti-HBe carriers is associated with a severe and evolutive liver disease and may provide an indication for treatment with drugs inhibiting the synthesis of HBV-DNA.