A 60-mo longitudinal study has been undertaken in 99 HBeAg-positive patients with clinicopathologically verified chronic hepatitis. Hepatitis B e antigen clearance occurred in 30 patients at a rate of approximately 17% per year. A phenomenon of abrupt elevation of serum glutamic pyruvic transaminase (greater than 300 IU/L) with histological changes compatible with chronic lobular hepatitis was observed in 13 of 20 patients (65%) preceding spontaneous HBeAg clearance. In contrast, 8 of 10 patients on immunosuppressive or antiviral therapy, or both, had uneventful HBeAg clearance. It was concluded that HBeAg clearance can occur in patients with varying immunologic status. The mechanism responsible for HBeAg clearance awaits further study.