Chronic myeloid leukemia; is the most common hematological malignancy worldwide. Its early treatment with imatinib; has greatly improved the prognosis of the disease to the degree that it is considered as a cornerstone therapy. However, resistance against imatinib has been developed. So, it is important to determine different causes of imatinib resistance to overcome it. The aim of current work is to study the role of SH2-containing tyrosine phosphatase-1 (SHP-1); mRNA expression & its promoter methylation in imatinib response in Egyptian chronic myeloid leukemia patients. Three groups were included in the study which are resistant, responder and control groups. Determination of expression level of SHP-1 was done using mRNA Quantitative reverse transcriptase polymerase chain reaction using Taqman assay. Determination of promoter methylation; of SHP-1 was done by methylation- specific polymerase chain reaction. It was found that SHP-1 mRNA expression level was significantly higher in the responder group than the resistant group and significantly higher in the control group than the resistant group but no significant difference was found between the responder and the control group. Also, there was a significant difference between the two groups (resistant and responder) regarding the methylation state of SHP-1 gene. Furthermore, Whole blood SHP-1 mRNA level was more sensitive biomarker in predicting imatinib response than SHP-1 methylation state. When combined together, SHP-1 mRNA and its methylation state showed better specificity but less sensitivity. Therefore, combined both SHP-1 mRNA and its methylation state can be used as biomarker for predicting response to imatinib among patients with chronic myeloid leukemia.