Mutations of BCR-ABL1 are observed in 50% of patients with Imatinib-resistant chronic myeloid leukemia (CML). The T315I mutation is resistant to imatinib and second-generation tyrosine kinase inhibitors (TKIs). We report the case of a 42-year-old male diagnosed with CML who acquired the T315I mutation while on Imatinib therapy. He was treated sequentially with combination therapy, comprising of interferon alpha and hydroxyurea which led to disappearance of the mutation and sustained haematological and major molecular response (MMR). To our knowledge, this is the first case report with a 12 year follow up showing the effectiveness of hydroxyurea/IFN combination therapy for CML patients bearing the T315I BCR-ABL mutation.