Background: IFNα can control erythrocytosis in 75% of PV while avoiding leukemogenicity of myelosuppressive drugs, but 20–25% of patients stop therapy due to side effects. Peg IFNα −2b, allowing weekly use, showed similar efficacy but no better tolerance in 3 trials. We conducted a phase 2 trial of peg-IFNα 2a in PV, a drug never tested in MPD to our knowledge. Study design: Inclusion criteria in PVN1 trial (www.clinicaltrials.gov as #NCT00241241). were PV diagnosis (PVSG criteria), age 18–65 years, no previous treatment or only phlebotomies, or cytoreductive treatment Results: 33 of the 40 pts enrolled had a 12 mos FU: M/F : 14/19, median age 50 yrs (range 22–65). Median time from diagnosis: 6 months (range 1–65). 9 pts (27%) had previously received HU, 6 (18%) had a history of thrombosis. Median Ht: 60% in males and 50% in females. Median WBC and plt counts: 9.109/l (range 4–23) and 598.109/l (range 171–1428), resp. 7 pts (21%) had splenomegaly. 1 patient was not evaluable for response (allergic reaction at first injection). At 6 mos, all pts were responders: 26 CR (81%), 6 PR (19%). At 12 mos, 2/32 pts had stopped treatment (1 grade 2 thrombocytopenia, 1 skin reaction), 27 (84%) were in CR and 3 pts in PR. Median peg-IFNα 2a dose received during the 1st year was 113 μ g/w (range 30–180). Neither thrombosis nor hemorrhage was reported. Only grade 1 to 3 toxicities were reported, lasting Conclusion: After 1 year, 94% hematological and 89% molecular response is obtained with peg-IFN-α 2a in PV, treatment being stopped due to side effects in only 9% of pts. Pts with 9pLOH had similar hematological and molecular response rates, although molecular response was slower. Peg-IFNα 2a could be a treatment of choice for PV, until specific targeted therapies are available.