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The generation of genetically modified mouse models with large DNA insertions remains a significant challenge. While current CRISPR/Cas9-based techniques are effective for smaller insertions, they often fail to reliably scale to larger DNA fragments. Traditional methods, such as recombinase-mediated cassette exchange (RMCE), can generate mouse models with insertions >100 kb starting with embryonic stem cells but are time-consuming, requiring at least six months to produce chimeras and an additional six months to breed these chimeras to homozygosity. Here, we present an optimized CRISPR-based strategy for the efficient insertion of DNA fragments exceeding 100 kb into the mouse genome via zygote injection. A key innovation of our approach is the use of long homology-directed repair (HDR) arms (20 kb each), which enhance the efficiency of integration, a significant departure from the standard shorter arms typically employed in CRISPR genome editing. We designed a bacterial artificial chromosome (BAC) vector containing a 155 kb fragment with human immunoglobulin heavy chain (IgH) V gene segments, flanked by 20 kb mouse homology arms. This method resulted in the precise and complete insertion of the 155 kb human IgH V gene segments, which recombined with the endogenous mouse D and J segments and paired with mouse immunoglobulin light chains. The engineered mouse model transmitted the inserted BAC DNA to its progeny in a Mendelian fashion. Immunization of these progeny with an influenza HA-stem immunogen induced robust immune responses, utilizing two of the inserted human IgH V segments, Ig VH1-69 and Ig VH1-69D, known to respond to HA stem, confirming that the KI was functional and demonstrating the potential of this model for studying humanized immune responses. Our strategy offers a simple, reliable, and scalable method for inserting large DNA fragments into the mouse genome, generating F0 mice bearing large inserts within three weeks. This approach facilitates the rapid generation of mouse models for the study of multigenic traits and the humanization of specific genomic loci in the mouse genome.