The interrelationship between hepatitis B virus (HBV) infection, hepatic injury and clinical activity in chronic HBV infection is incompletely understood. We have scored histologic activity, the expression of hepatitis B core (HBcAg) and hepatitis B surface antigen (HBsAg) and assessed HBV replication to correlate HBV antigen expression with histologic disease. Forty-seven formalin-fixed, percutaneous liver biopsies from HBeAg carriers were studied. Twenty-nine were Black, 16 Caucasian and two Oriental. Fifty-nine percent had chronic active, 35% chronic persistent hepatitis and 14% cirrhosis. None were positive for antibodies to Human Immunodeficiency Virus (HIV). HBsAg and HBcAg in tissue were detected by immunochemical staining. Diffuse HBsAg staining was observed in 10/15 patients with CPH, but there was no correlation between histologic score and HBsAg expression. Intracytoplasmic HBcAg was observed in patients seroconverting to anti-HBe, but was also detected in patients with minimal hepatitis. An inverse correlation between histologic score and HBcAg expression was observed. HBcAg expression was more widespread in patients with CPH (mean 37%) than in CAH (mean 18%). A positive correlation was observed between serum aminotransferase concentrations and histologic score. Although no consistent pattern can be discerned, HBcAg expression and hepatic injury are frequently dissociated in patients with chronic HBV infection; complex host responses may determine the variable degree of disease activity and hepatic injury.