Myeloproliferative Neoplasms (MPNs) are clonal disorders characterized by the presence of several gene mutations associated with particular hematological parameters, clinical evolution and prognosis. Few therapeutic options are available, among which Interferon alpha (IFNα) presents interesting properties like the ability to induce hematological and molecular responses in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). Hematological response was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and two patients even achieved complete molecular response. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2 and TP53 genes). The presence of additional mutations was associated with poorer molecular response on CALR mutant clones, with only minor or no molecular responses in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of hematological and molecular responses in CALR-mutated ET, and that the presence of additional non-driver mutations may influence the molecular response to therapy.