The serological endpoint of response in the treatment of chronic hepatitis B is the loss of hepatitis B virus DNA and HBeAg. Because the quantitative measurement of hepatitis B virus DNA in serum has been shown to be useful for monitoring and predicting response to interferon-a therapy, we decided to evaluate whether changes in HBeAg concentration could also be used in this manner. Twenty-nine patients who were initially positive for HBeAg and HBV DNA were serially evaluated for HBeAg concentration with a microparticle-capture enzyme immunoassay. HBeAg levels in serum were calculated by means of comparison with a standard curve of fluorescence rate vs. HBeAg concentration. The results, expressed in milliunits per milliliter, were compared with hepatitis B virus DNA levels determined by means of solution hybridization. The baseline HBeAg concentration proved to be the best independent predictor of response on stepwise Cox regression analysis (p = 0.026). Similar disappearance curves were observed for the two markers, although hepatitis B virus DNA became undetectable at an earlier interval in 13 of 16 cases (81%). In the 16 responders, a decline in HBeAg concentration of more than 90% was observed by wk 12 of therapy (mean 2 S.D., 95% f 13%). Nonresponders did not demonstrate such steep declines in HBeAg values by wk 12 (mean f S.D., 45% 2 27%), and levels tended to increase at subsequent time points. We conclude that serial monitoring of HBeAg concentration with a technique that should be readily adaptable to clinical laboratories may be useful in the initial evaluation and monitoring of patients undergoing antiviral therapy.