Survival in chronic myeloid leukemia (CML) was dramatically improved by development of tyrosine kinase inhibitors (TKIs) directed to the BCR::ABL1 oncogene. Unfortunately, ~30% of CML patients develop TKI-resistance during prolonged treatment, with enhanced blast crisis risk. Oxidation Resistance 1 (Oxr1) regulates anti-oxidant pathways that detoxify reactive oxygen species (ROS) generated by the phagocyte-NADPH oxidase. In the current studies, we found that Oxr1 expression increased in hematopoietic stem and progenitor cells (HSPCs) from CML mice versus controls; decreased during TKI-induced remission; and rose during chronic phase relapse. Oxr1 has long and short isoforms, and we found increased short, but decreased long, Oxr1 in mice or humans during CML relapse. We determined long Oxr1 prevents ROS accumulation in CML marrow, but short Oxr1 is a dominant negative. Previously, we found exaggerated and sustained emergency granulopoiesis in CML mice, with repeated episodes facilitating relapse during TKI-remission. In the current studies, we found knocking-down Oxr1 in murine marrow further accelerates CML progression during this physiologic stress. We found increased DNA-damage in HSPCs from these mice, including a BCR::ABL1 kinase-domain mutation found in TKI-resistant human CML. These studies suggest long Oxr1 detoxifies ROS to decrease mutagenesis in CML, but aberrant short Oxr1 expression enhances progression.