AIM: To evaluate the clinical efficacy and safety of pegylated interferon-alpha (Peg-IFN-α) in the treatment of essential thrombocythemia (ET). METHODS: A total of 50 ET patients were treated with Peg-IFN-α for more than 12 months. 180 μg was injected subcutaneously once every two weeks as the initial dose, and then the treatment interval was adjusted according to blood routine. The clinical efficacy and adverse reactions were analyzed. RESULTS: The hematologic response of ET patients treated with Peg-IFN-α occurred quickly, and the platelet decreased significantly after 3 months (508.56±120.75 vs. 931.44±209.13, P=0.000). Hematologic complete remission rate and overall remission rate at 12 months were 70% and 98%, respectively. The JAK2-V617F mutation burden of ET patients treated with Peg-IFN-α was significantly lower at 6 months of treatment than at initial diagnosis (0.254 1±0.122 8 vs. 0.315 3±0.133 2, P<0.000 1). The 1-year molecular biology complete remission rate was 12.5%, and overall remission rate was 31.75%. MPN-SAF-TSS scores decreased significantly within 6 months after Peg-IFN - α treatment (P< 0.001), but there was no significant change in the score at 12 months compared with 6 months (P> 0.05). Hematological adverse reactions were rare, and all of them were grade 1-2 adverse reactions. Non-hematological adverse reactions were mainly influenza-like symptoms. Most of the patients were grade 1-2, and occasionally had grade ≥3 adverse reactions. All adverse reactions could be tolerated after extending medication interval or symptomatic treatment, and no patient terminated treatment because of adverse reactions. CONCLUSION: Peg-IFN-α is effective and safe in the treatment of ET.