Summary. To reduce unnecessary exposure to treatment, physicians must decide at an early stage whether continuation of treatment has a reasonable chance of success for the individual patient. The objectives of our study were to evaluate the previously described quantitative hepatitis B e antigen (HBeAg) measurements vs quantitative hepatitis B virus (HBV) DNA measurements for prediction of nonresponse and response in interferon (IFN)-α treated HBeAg positive chronic HBV patients. Serum HBV DNA and HBeAg levels were assessed at baseline and weeks 8 and 12. For each test (HBV DNA level at baseline, HBV DNA decrease between baseline and weeks 8 and 12, or the combination of these two, as well as HBeAg level at baseline, HBeAg decrease between baseline and weeks 8 and 12, and the combination of these two), we calculated the positive predictive value, negative predictive value, sensitivity and specificity. Monitoring with quantitative HBV DNA levels (area under ROC 0.87) was superior to monitoring with quantitative HBeAg levels (0.76, P < 0.05). Step-wise logistic regression identified HBV DNA at baseline and decrease in HBV DNA from baseline to week 12, as independent predictors of response. The overall test performance of predicting nonresponse (predictive value 100%) was best for log HBV DNA testing at week 12 compared with testing at week 8 due to a better prediction of sustained response (46%vs 38%) and lower misidentification of nonresponse (39%vs 54%). This study showed that quantitative HBV DNA testing at baseline in combination with a decrease between baseline and week 12 has a high predictive value for identifying patients who have virtually no chance of reaching a sustained response with IFN therapy.