To prevent thrombosis in patients with polycythemia vera (PV), achieving a complete hematologic response (CHR) is highly recommended in practice. In addition, a reduced JAK2 V617F mutation burden is expected to have a disease-modifying effect, and its molecular response (MR) is currently of significant interest. This study aimed to assess the association between CHR and MR in patients with PV following treatment with ropeginterferon alfa-2b. This phase 2, single-arm, open-label, investigator-initiated trial was conducted at 16 sites in South Korea. Ninety-nine patients were treated with ropeginterferon alfa-2b subcutaneously every 2 weeks, at doses of 250 μg (week 1), 350 μg (week 3), and 500 μg (week 5), until week 48. CHRs were 27% (25/94), 46% (40/87), 56% (47/84), and 63% (51/81) at 12, 24, 36, and 48 weeks, respectively. The MR rates were 32% (28/88), 36% (29/81), 49% (38/77), and 57% (42/74) at 12, 24, 36, and 48 weeks, respectively. The Phi Coefficient for the association between CHR and MR was 0.6146 (p <
.0001) at 48 weeks. In the subgroup analysis, patients with hydroxyurea resistance or intolerance, and those who were hydroxyurea-naïve, had similar results in terms of the CHR. In conclusion, CHR and MR were observed to be associated in patients with PV treated with ropeginterferon.