Ex vivo gene editing holds promise for precise gene correction in human hematopoietic stem/progenitor cells (HSPCs), albeit hurdles remain for clinical application. Targeted integration of therapeutic DNA sequences by Cas9 nuclease and homology-driven repair (HDR) is limited by low efficiency and occurrence of potentially genotoxic editing outcomes (e.g. long-range deletions). Nickase-based platforms, e.g. base/prime editors (B/PEs), have been poorly studied in terms of efficiency, adverse impacts and genotoxicity. Here, we optimized a HDR editing protocol based on Integrase-Defective Lentiviral Vector (IDLV) yielding higher HDR efficiency, reducing cytotoxicity and mitigating the genotoxic risk associated to integration of vector DNA fragments. Moreover, we developed a versatile platform for positive selection of cells bearing the HDR edit based on transient Selector expression by Means of Artificial Transactivators (SMArT). SMArT enriched HSPCs edited at ~30% to nearly 100% and significantly purged out cells bearing on-target long-range deletions. Selected cells yielded a fully edited human xenograft with no longer selector expression. We then assessed BE and PE vs. Cas9 in HSPCs and found that B/PE induced multifaceted transcriptional responses constraining efficiency and HSPC repopulation in xenotransplants, albeit to lesser extent than Cas9. DNA double-strand breaks and their genotoxic byproducts were less frequent but not abrogated by B/PE, particularly for cytidine BE due to suboptimal inhibition of base excision repair. Tailoring timing and B/PE expression enabled highly efficient and precise editing. Yet, we uncovered a genome-wide effect of cytidine BE on the mutational landscape of hematopoietic grafts, raising concerns for its clinical application. Conversely, adenine BE showed superior efficiency and precision. These results highlight limitations of existing editing platforms and provide strategies to overcome them in view of clinical translation.