We have separated circulating HBeAg into small and large molecular forms by agarose gel electrophoresis and analyzed the relationship between the two forms and other clinical features of chronic hepatitis B, especially in regard to liver cell damage. The large HBeAg accounted for 7.3% ± 3.4% of serum HBeAg in 9 subjects with normal liver histological findings or nonspecific reactive hepatitis, 38.0% ± 27.8% in 32 patients with chronic persistent hepatitis and 65.6% ± 23.3% in 21 patients with chronic active hepatitis (p < 0.01). A positive correlation was seen between the height of aminotransferase elevations and the percentage of large HBeAg. Three patients who progressed from histologically normal liver or nonspecific reactive hepatitis to chronic active hepatitis had dramatic increases in the percentage of large HBeAg. The finding that the presence of large HBeAg in serum correlated with the severity of hepatitis suggests that HBeAg may play an important role in determining the degree of liver injury in chronic hepatitis B. (HEPATOLOGY 1991;13:1057–1060.)