Introduction Interferons, pegylated interferons (PegIFN), and oral antivirals are used in the treatment of chronic hepatitis B (CHB) virus infection. The number of studies comparing the efficacy of PegIFNs in the treatment of HBe antigen-negative CHB is rather limited. In this trial, the efficacy of two PegIFN products used in the treatment of CHB is compared. Methods Study data were obtained from 16 tertiary healthcare service centers located in various areas of Turkey. Data of patients who were consecutively treated with PegIFN alpha-2a or alpha-2b for CHB were recorded retrospectively. Hepatitis B virus DNA and liver enzymes were analyzed at the beginning of the treatment and during weeks 12, 24, 48, and 72. A P-value less than 0.05 was considered to be significant. Results A total of 155 patients were enrolled in this trial. Two cases were excluded because of insufficient data. Among the remaining 153 patients, 81 (53%) patients were in the PegIFN alpha-2a group and 72 (47%) patients were in the alpha-2b group. Treatment success was found to be 17.2% for the PegIFN alpha-2a group and 18.0% for the PegIFN alpha-2b group (P>0.05). In terms of efficacy (weeks 24, 48, and 72), there were no significant differences between the groups (P>0.05). Conclusion According to our results, for HBe antigen-negative CHB cases, the response rate during the sixth month after the treatment with PegIFN was determined to be similar to 17%. No difference was found between the efficacy rates of the two PegIFN products used in the treatment of HBe antigen-negative CHB. Eur J Gastroenterol Hepatol 24: 1296-1301 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.