Two hundred forty-two voluntary blood donors, referred after detection of HBsAg positivity, underwent clinical evaluation and liver biopsy and were prospectively followed for an average of 3.5 years. At initial testing, 65% of HBsAg carriers had normal laboratory findings; during follow-up, 26% of these carriers developed abnormal test results, at least transiently. Liver histology was normal in 31.4%, revealed nonaggressive liver disease in 63.6% and chronic active hepatitis or cirrhosis in 5%, only. All except one case of chronic active hepatitis or cirrhosis were associated with abnormal blood biochemical tests. Sequential liver biopsies obtained in 56 HBsAg carriers after a minimal interval of 4 years showed mitigation of inflammatory changes in 5.4% and developing chronic active hepatitis in three cases (5.4%). One carrier died of primary hepatocellular carcinoma. Upon follow-up, HBsAg persisted in 98%. Anti-HBe was found in 90% of all carriers already at the initial testing. HBeAg positivity (7.5%) was associated with chronic active hepatitis as well as nonaggressive liver disease; clearance of HBeAg occurred in 40% after 2 to 8 years. Because of the subclinical progression of liver disease and the increased risk for developing primary hepatocellular carcinoma in asymptomatic HBsAg carriers, routine blood testing, including alpha-fetoprotein screening, as well as abdominal ultrasound surveillance are indicated. Liver biopsy, however, should be restricted to carriers with abnormal biochemical findings.