Background: Chronic myeloid leukemia is a clonal myeloproliferative disease which is characterized by bcr/abl translocation. With the emergence of tyrosine kinase inhibitors such as imatinib mesylate, significant improvement has been made in treatment of this disease. However, drug resistance against this medicine is still an obstacle. SIRT1 is a gene with deacetylase activity which has been detected to have increased expression in many cancers. We aimed to determine if SIRT1expression could play a role in the emergence of drug resistance in patients with chronic myeloid leukemia being treated with imatinib mesylate. Methods: 48 patients with chronic myeloid leukemia referred to Dr. Shariati Hospital, Tehran, Iran, were studied. A venous blood sample of patients was collected, RNA was extracted and then cDNA were synthesized. SIRT1 gene expression was done by real-time PCR. The ratio of SIRT1 expression to ABL control gene was calculated. After calculation of CT for target gene and control gene, &DeltaCT was calculated. The results of SIRT1 expression levels in patients with chronic phase of CML were compared with that of the control group. Results: 48 patients with chronic myeloid leukemia aged 15-64 years (mean: 40 years) were enrolled. 59% of the participants were men. The highest and lowest mean BCR-ABL expressions in drug-resistant patients were 1% and 57%, respectively. The results of analyzing the value of &DeltaCT for SIRT1 gene revealed that patients who were drug-resistant to imatinib mesylate had a lower value of &DeltaCT for SIRT1 than those who were not drug-resistant (P<0.05). Conclusion: SIRT1 gene expression in patients resistant to imatinib mesylate was significantly higher than patients who were not drug-resistant.