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Background Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. We sought to improve the diagnostic armamentarium by screening and to analyze the dynamics of mutated clones in chronic myeloid leukemia patients who experienced hematologic or cytogenetic relapse.Design and Methods Ninety-five patients who relapsed during imatinib therapy were screened for BCR-ABL kinase domain mutations using sensitive denaturing high-performance liquid chromatography (D-HPLC) and direct sequencing. To investigate the dynamics of mutated clones D-HPLC was applied to 453 cDNA samples tracking back from relapse towards the start of imatinib therapy.Results Twenty-two different point mutations affecting 18 amino acids were detectable in 46/79 (58%) and in 7/16 patients (44%) with hematologic or cytogenetic relapse, respectively. A deletion of 81 nucleotides (del248-274) of ABL exon 4 was observed in two patients. Three patients had exclusively single nucleotide polymorphisms (K247R, T315T, E499E, n=1 each) within the BCR-ABL kinase domain. In patients harboring mutations, hematologic relapse occurred after a median of 12.9 months (range, 0.9–44.2), and BCR-ABL mutations first became detectable at a median of 5.8 months (range, 0–30.5) after starting imatinib therapy (p