Objective To investigate the characteristics of baseline bone marrow chromosome karyotype analysis in patients with chronic-phase chronic myeloid leukemia (CML) and its predictive value for tyrosine kinase inhibitor (TKI) treatment response and long-term prognosis. Methods This retrospective prognostic study included 120 newly diagnosed chronic-phase CML patients from Zhengzhou KingMed Clinical Laboratory from January 2022 to December 2025. All patients underwent bone marrow G-banding karyotype analysis and received imatinib-based first-line TKI therapy. According to the therapeutic effect after 3 months of treatment, the patients were grouped as follows: BCR-ABLIS≤10% as the optimal response group (85 cases), and ＞10% as the warning/failure group (35 cases). Cytogenetic response rates, molecular response rates, and karyotype evolution were compared across different karyotype subgroups. Kaplan-Meier analysis with the log-rank test and univariate Cox regression were used to identify prognostic factors for progression-free survival (PFS). Results Among the 120 patients, the Ph chromosome positivity rate was 98.33%, and the rate of additional chromosomal abnormalities (ACA) was 23.33% (major-route abnormalities: 20 cases; minorroute abnormalities: 8 cases). The complete cytogenetic response rate in the ACA group (57.14%) was significantly lower than that in the Ph-only group (82.61%) (P＜0.05). The 1-year major molecular response rate was also significantly lower in the ACA group (42.86% vs. 77.17%, P＜0.05). Univariate analysis identified baseline ACA as a significant risk factor for PFS (HR＝3.42, P＝0.002). The 3-year PFS rate was superior in the Ph-only group compared with the ACA group (94.5% vs. 71.4%, P＜0.001). The rate of karyotype evolution during treatment was significantly higher in the warning/failure group than in the optimal response group (34.29% vs. 5.88%, P＜0.05). Conclusion Baseline major-route ACA is an independent adverse prognostic factor for poor TKI response and disease progression in CML patients, with prognostic value complementary to the European Treatment and LeukemiaNet Score (ELTS). Karyotype evolution during treatment may serve as an early warning signal of drug resistance and progression, providing guidance for clinical guidance of individualized treatment.