We reviewed 261 patients with chronicphase chronic myelogenous leukemia (CML) after interferon-alpha (IFN-alpha) failure treated with imatinib mesylate 400 mg daily. With a median follow-up time of 45 months, the major cytogenetic response rate was 73% and the complete cytogenetic response rate 63%. The estimated 4-year survival rate was 86%. Multivariate analysis for survival identified hematologic resistance to IFN-alpha (P =.01), splenomegaly (P =.03), and lack of any cytogenetic response after 3 months of therapy (P =.01) to have independent poor prognostic significance. Patients could be divided into good (no adverse factors), intermediate (1 adverse factor), and poor-risk groups (2 or 3 adverse factors; 12% of patients) with estimated 4-year survival rates of 96%, 86%, and 49%, respectively (P <.00001). The 4-year cumulative major molecular response (quantitative reverse transcriptase-polymerase chain reaction [Q-PCR] = BCR-ABL/ABL less than 0.05%) rate was 43% and complete molecular response rate (BCR-ABL undetectable) 26%. Compared with a historical group of 251 similar patients treated with nonimatinib therapies, imatinib mesylate was associated with a better 4-year survival rate (86% versus 43%; P <.0001); the survival advantage was confirmed by multivariate analysis (hazard ratio, 0.19; P <.0001).