Polycythemia vera (PV) is characterized by the presence of the JAK2V617F mutation in virtually all patients. Several studies have shown that the JAK2V617F mutational load decreases during treatment with alpha-interferon 2. We report on molecular and histomorphological bone marrow responses in seven PV patients with profound molecular responses during and after long-term treatment with alpha-interferon 2b. All patients obtained a major molecular response (MMR). Subsequently all patients discontinued alpha-interferon and sustained complete hematological remission with a follow-up period of median 10 months (range 4-30 months). Complete normalization of the bone marrow was seen in three of five patients. Long term treatment with IFN2b is able to induce 'minimal residual disease' with very low JAK2 V617F allele burden and may induce profound, and in some patients total, regression of histomorphological bone marrow features of PV. Finally, hematological remissions and major molecular responses can be sustained after discontinuation of long-term treatment with IFN2b.