Treatment of von Willebrand disease (VWD) has been topic of discussions and research for several decades. The (genetic) heterogeneity of the inherited bleeding disorder remains one of the biggest obstacles for proper treatment, as well as the high costs of (recombinant) factor concentrates of VWF. In this study we present a personalized gene therapy approach for heterozygous VWD type 2 patients that has been inspired by previous research on allele-selective siRNA targeting of mutant VWF. However, instead of siRNAs, we designed allele-selective gRNAs that are capable to selectively remove the allele carrying the pathogenic variant using CRISPR-Cas9. By targeting a common heterozygous SNP on the mutant allele, the strategy holds the possibility to find a broader application among patients, while being personalized at the same time. The results in our ex vivo model of patient-derived endothelial colony forming cells (ECFCs) show a strong allele-selectivity and a rescue of the disease phenotype in these cells. Proteomic analysis and next generation sequencing (NGS) validate the phenotypic observations and suggest this approach as a promising gene therapeutic strategy for future treatment of heterozygous VWD patients.