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Nucleos(t)ide analogues are first-line therapies for the treatment of chronic hepatitis B. However, the efficacy and safety of long-term treatment and the necessary duration of therapy remains the subject of discussion. Aim. To assess the efficacy and safety of long-term treatment with nucleos(t)ide analogues in patients with chronic hepatitis B. Materials and methods. We conducted an observational study in 101 chronic hepatitis B (HBeAg-negative and HBeAg-positive) patients treated (≥3 years) with entecavir, tenofovir or telbivudine. Results and discussion. Treatment with entecavir and tenofovir was associated with high rate of virologic and biochemical response (>95%) and HBeAg seroconversion (93% and 67%, respectively). Cumulative rate of virologic resistance was 0; 3.1% and 43.5% for tenofovir, entecavir and telbivudine, respectively. Long-term nucleos(t)ide analogues treatment resulted in a regress of liver fibrosis (from 8.92 to 7.18 kPa, р