Hepatitis B virus (HBV) infections and sequelae present significant health problems worldwide. Two groups of medications are available for chronic HBV infection treatment: (1) interferons (IFNs) and (2) nucleos(t)ide analogues. This study aimed to evaluate entecavir (ETV) and tenofovir disoproxil fumarate (TDF) efficacies in chronic HBV patients, who achieved virological response during Peg-IFN treatment but did not sustain this response and relapsed a year after treatment end. In this study, 74 patients with chronic HBV infection who had virological responses to 180 mu g/week Peg-IFN alpha-2a treatment were included; 38 (20 and 18 HBeAg positive and negative, respectively) of these patients were treated with 245 mg/day TDF, and 36 (20 and 16 HBeAg positive and negative, respectively) were treated with 0.5 mg/day ETV upon relapse after initial treatment discontinuation. In HBeAg-positive patients biochemical response rates were higher for TDF at weeks 96 and 144 (p = 0.044 and 0.019, respectively). However, biochemical response rates were similar for TDF and ETV in HBeAg-positive and HBeAg-negative groups at other weeks (p > 0.05). Virological and serological response rates were similar in patients treated with TDF and ETV in HBeAg-positive and HBeAg-negative groups (p > 0.05).