Hematopoiesis is maintained by a polyclonal pool of hematopoietic stem cells (HSCs). Single somatic mutations in recurrent genes cause the emergence of expanded clones in elderly persons, a phenomenon called clonal hematopoiesis of indeterminate potential (CHIP). While the multilineage differentiation of these clones suggests an involvement of HSCs in CHIP, direct evidence of the fitness of CHIP-mutated human HSCs in blood reconstitution is lacking. Interestingly, previous studies showed a constant clone size for decades under steady-state conditions. Myeloablative treatments and stem cell transplantation put enforced stress on HSCs to reconstitute the blood system, and the fitness of HSCs is challenged. To assess whether human CHIP-mutated HSCs outcompete their wildtype counterparts in stress hematopoiesis, we took advantage of a well-characterized cohort of currently 81 patients undergoing high-dose chemotherapy conditioning and autologous stem cell transplantation (autoPBSCT) for the treatment of solid tumors or lymphoid diseases in our center. Using deep next generation sequencing of 56 myeloid cancer genes, we found that 17 patients (21%) are affected by CHIP (variant allele frequency >2%) in their blood at a time 6–102 months after autoPBSCT, with a mean variant allele burden of 4.5%. To explore whether the mutations had been present before the high-dose chemotherapy, and whether the CHIP-mutated HSCs expanded after autoPBSCT, we sequenced the frozen samples of the transplanted grafts. Importantly, the mutations can be detected in the majority of patients already in the transplanted cells, suggesting that they are not induced by high dose chemotherapy; however, the allele burden in the graft is significantly lower, often below 0.5%, than in the blood months to years after autoPBSCT suggesting a selective advantage of mutated HSCs outcompeting normal HSCs upon stress hematopoiesis. Ongoing functional evaluations will reveal CHIP-related differences in HSC behavior and lineage choice at single HSC resolution using time-lapse microscopy-based cell tracking and in vivo competitive transplantations, to elucidate the causative of CHIP-related disorders.