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Background: Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results: Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities. Treatment with ponatinib in the frontline setting of chronic myeloid leukemia in chronic phase was associated with high molecular response rates, with 12‐month cumulative rates of major molecular response and MR4 of 82% and 72%, respectively. However, it was associated with an increased incidence of toxicity, in particular serious grade 2‐3 cardiovascular adverse events in 16% of the patients. [ABSTRACT FROM AUTHOR]