Polycythemia vera (PV) is characterized by clonal hematopoietic stem or progenitor cells with constitutively active somatic mutation(s) in the Janus kinase 2 gene. Phlebotomy (Phl) and aspirin are often used alone for low-risk PV patients. However, data from the Low-PV study demonstrated that Phl and aspirin may not be adequate for patients. Therapeutic intervention with disease-modifying treatment appears to be beneficial for patients with PV regardless of the risk category. Ropeginterferon alfa-2b (ropeg) is a novel interferon-based therapy with favorable dosing schedules. A higher starting-dose (250 µg) regimen with simpler dose titrations was found to have a potent disease-modifying effect with respect to inducing a molecular response. PARADIGM-PV is a randomized, phase 4 study with the primary goal of assessing the efficacy of ropeg at this dosing regimen in alleviating Phl-dependence in both low- and high-risk patients with PV. The secondary endpoints include complete hematologic response, molecular response, symptom improvement, maintenance of median hematocrit (Hct) values < 45% without disease progression, and safety. Patients will be randomized equally to receive either ropeg every two weeks or to continue their current treatment with Phl or other cytoreductive agents (e.g., hydroxyurea, other interferons, or ruxolitinib) as applicable. All patients will receive Phl if their Hct values are elevated to ≥45% according to the National Comprehensive Cancer Network guidelines. The study will enroll approximately 70 patients internationally, including patients in the US. This study will provide new efficacy data, measured as the ability of ropeg to reduce Phl eligibility and modify the disease.