Imatinib‑based targeted treatment is the standard therapy for chronic myeloid leukemia (CML); however, drug resistance is an inevitable issue for imatinib‑based CML treatment. Imatinib resistance can be ascribed to Bcr‑Abl‑dependent and independent resistance. In the present study, peripheral blood samples were collected from imatinib‑sensitive (IS) and imatinib‑resistant (IR) CML patients and transcriptome sequencing was carried out. From the RNA‑seq data, a significantly altered IR‑related gene (IRG), ribonucleotide reductase regulatory subunit M2 (RRM2) was identified. Using real‑time quantitative fluorescence PCR (qF‑PCR), we found that RRM2 was elevated in both IR CML patients and an IR cell line. Using reverse‑transcription PCR (RT‑PCR) and western blot analysis, we indicated that imatinib can increase RRM2 level in a dose‑dependent manner in IR cells. We also demonstrated that RRM2 is involved in the Bcl‑2/caspase cell apoptotic pathway and in the Akt cell signaling pathway, and therefore affects the cell survival following imatinib therapy. The present study, for the first time, indicates that RRM2 is responsible for drug resistance in imatinib‑based therapy. Therefore, RRM2 gene can be considered as a potential therapeutic target in the clinical treatment of CML.