BACKGROUND: Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B infection has a presentation and clinical course that is divergent from that of HBeAg‐positive infection. The former usually presents with lower viral levels but faster progression to liver disease. We sought to better understand the balance between replication and the immune response against hepatitis B virus (HBV). METHODS: Viral kinetics in 50 HBeAg‐negative patients under various treatment protocols with interferon α and/or nucleoside or nucleotide analogs was analyzed. HBV DNA level was measured frequently and the data fitted to a viral dynamic model. A meta‐analysis of all published studies of viral kinetics in HBeAg‐positive and HBeAg‐negative infection was also conducted. RESULTS: We found that the clearance of both HBV virions and infected cells was significantly faster in HBeAg‐negative infection than in HBeAg‐positive infection. In HBeAg‐negative infection, there was also a negative correlation between baseline HBV DNA levels and infected cell half‐life, suggesting that the higher the viral load the faster the turnover of infected cells. CONCLUSIONS: These results reveal the dual role played by the immune response in maintaining lower viral levels and inducing faster turnover of infected cells, the latter of which may be responsible for the more aggressive nature of HBeAg‐negative infection.