Background: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. With the advent of 2nd generation TKI and the now available choice of drugs, safety issues have gained interest. Methods: We have used 1,551 patients of the randomized CML-Study IV for a long-term safety and efficacy evaluation of imatinib. Adverse drug reactions (ADR) were reported at each follow-up visit, coded and graded according to the NCI CTC AE list. Molecular analysis for residual BCR-ABL transcripts was adjusted by the international scale. Results: 1,501 patients have received imatinib and were evaluable. Median age at diagnosis was 53 years, 88 % were EUTOS low risk. At the last evaluation (04/11/2013) 1,003 patients still received imatinib, 164 have died, 275 have been switched to a 2nd generation TKI, 106 have been transplanted (numbers in part overlapping). The longest observation time was 11.5 years, the median observation time 6.5 years. Efficacy: 10-year progression-free and overall survival probabilities were 81% and 84%, respectively. 10-year cumulative response rates reached 89% for MMR, 81% for MR⁴, 74% for MR^4.5 and 63% for MR⁵. Safety: In 1,018 out of 1,375 patients (74%) non-hematologic ADR were reported during imatinib treatment, in 193 grade 3/4 ADR (14%); 8-year probabilities (all grades) were: fluid overload or edema 41 (36–46)%, gastrointestinal 38 (34–43)%, myalgia or arthralgia 25 (21–29)%, rash 20 (17–24)%, musculoskeletal 17 (13–22)%, fatigue 17 (13–20)%, neurological 11 (8–13)%, and flu-like 10 (8–13)%. Probability profiles over time have been generated for each ADR. In 5 patients peripheral arterial occlusive disease grade 2 or 3 was reported, but none could be clearly assigned to imatinib. A definite association between any ADR and death was not found. Most patients had their first ADR during the first three years with decreasing frequency later on. Conclusions: Given that no imatinib-related death was recorded and that grade 3/4 ADR could typically be symptomatically improved and tolerated we consider imatinib a safe, comparably well tolerated TKI even after prolonged treatment. After 10 years imatinib continues to be an excellent choice for the treatment of CML in most patients. Clinical trial information: NCT00055874.