Background: Flumatinib is a novel second-generation tyrosine kinase inhibitor (2G-TKI), which was approved in November 2019 in China. A previous phase III study evaluated the efficacy and safety of flumatinib as a first-line therapy for patients with chronic phase chronic myeloid leukemia (CML-CP). However, randomized trials comparing flumatinib with other 2G-TKIs remain lacking. Objectives: To assess the efficacy and safety of flumatinib versus nilotinib as a first-line treatment for CML-CP. Design: A multicenter retrospective study. Methods: We retrospectively analyzed 101 and 64 patients treated with flumatinib and nilotinib during the same period, respectively. Results: Patients in the flumatinib group were significantly older than patients in the nilotinib group (median age, 44 vs 37 years; p = 0.004). The optimal response and treatment failure rates at 24 months were comparable between the two groups. At 12 months, 85.1% and 88.2% of patients in the flumatinib and nilotinib groups, respectively, achieved a major molecular response (MMR; p = 0.648). By 24 months, 9.9% and 12.5% of patients suffered treatment failure in the flumatinib and nilotinib groups, respectively ( p = 0.602). At 9, 12, and 24 months, the rate of MR 4 (a BCR::ABL1 transcript level ⩽0.01%) achievement was significantly higher in patients treated with nilotinib than in those treated with flumatinib (26.0% vs 53.7%, p = 0.007; 40.4% vs 60.8%, p = 0.044; and 41.7% vs 80.8%, p = 0.042, respectively). In addition, elevated alanine aminotransferase or aspartate aminotransferase (ALT/AST), glucose, and serum lipid; hyperbilirubinemia; rash; and alopecia were more frequent among patients receiving nilotinib, whereas diarrhea was more frequent in those receiving flumatinib. Conclusion: Flumatinib is a suitable alternative as a first-line treatment for patients with CML-CP to achieve a fast MMR with better tolerability.