Abstract Imatinib (standard dose, SD, 400mg/day) is highly effective in patients with CML in early chronic phase (CP). However, in a phase I study there was clear dose-response correlation and no maximum tolerated dose was identified up to 1000mg/day. Early reports suggested higher response rates with high dose (HD) imatinib (800 mg/day) in this setting. Here we report the long-term follow-up results of high-dose imatinib for patients with CML in early CP. Patients were included from 3 sequential trials: the first included 50 patients all treated with 400mg daily, and 2 subsequent studies included 208 patients all treated at 800 mg daily as the starting dose. There were no differences in pre-treatment characteristics between HD group and SD groups. The median age was 48 years in both groups. Median follow-up was 58 months for SD and 34 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (91% vs 76% in SD group, p=0.002) and these occurred earlier, with 88% achieving a complete cytogenetic response (CGCR) after 6 months of therapy (vs 56% with SD; p<0.00001). The cumulative incidence of major molecular response (MMR) was significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 33%, 58%, 82% and 88% of patients had achieved this response at each time point (vs 2%, 22%, 64% and 67% in the SD group; p<0.00001, <0.00001, 0.01 and 0.002 at respective time point). The cumulative incidence of complete molecular response (CMR) was also significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 8%, 20%, 53% and 66% of patients had achieved this response at each time point (vs 0%, 4%, 27%, and 34% in the SD group; p=0.05, 0.007, 0.003 and 0.0006 at respective time point). Progression-free and transformation-free survivals were significantly better in HD group (p=0.02 and 0.005). Overall survival was excellent in both groups with no difference between them. Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in both groups. The frequency of ≥ grade 3 anemia, neutropenia and thrombocytopenia in HD group was 12, 35, 29%, respectively while those in SD group were 4, 20, and 12%, respectively. The median actual dose in HD group was 800 mg at 24 months, with only 20% (15/75) of patients taking 400 mg or less at 36 months. We conclude that high-dose imatinib therapy in early CP-CML is associated with higher rates of CGCR, MMR and CMR, and these occur earlier, translating into better progression-free and transformation-free survival. Although HD imatinib is overall well tolerated, there is a higher rate of myelosuppression, most frequently occurring during the first weeks of therapy.