Backgroud: Tyrosine kinase inhibitors (TKIs) has gradually replaced HSCT as the first-line treatment for pediatric patients with chronic-phase Chronic myeloid leukemia (CML-CP). However, there are few reports detailing the long-term effect and safety of TKIs in Chinese children with CML-CP. Procedure: A total of 58 patients (43 children and 15 adolescents) with newly diagnosed CML-CP received imatinib mesylate (IM) as first-line therapy and 2G-TKIs as second-line therapy. The responses and safety to TKI therapy, and the rates of overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) were assessed. Results: After 3 months of IM treatment, 91.4% (53/58) of patients achieved complete hematologic response (CHR). Fifty-one patients received further IM treatment for up to 12 months, and 88.2% (45/51) of them achieved major cytogenetic response (MCyR), with 68.6% (35/51) achieving complete cytogenetic response (CCyR). The cumulative incidence of achieving major molecular response (MMR) was 45.1% (23/51) and 66.0% (31/47) after 12 months and 18 months from initial IM treatment, respectively. Sixteen patients were switched to second-generation TKIs (2G-TKIs), dasatinib (n=8) and nilobinib (n=8), due to lack of response to IM treatment. Among them, 11 patients (68.8%) achieved MMR at a median time of 3.7 months. With a median follow-up duration of 44.8 months, the 9-year overall survival rate (OS) was 81.1%, the 9-year progression-free survival rate (PFS) was 80.5%, and the 9-year event-free survival rate (EFS) was 44.4%. Conclusion: IM as first-line therapy and 2G-TKI as second-line therapy are effective long-term therapeutic measures for children and adolescents in CML-CP.