Graft rejection is an important concern following haploidentical transplant with a reported incidence of 10-15%. The number of human leukocyte antigen (HLA) mismatches and the vector of mismatch have not been found to be associated with the risk of graft rejection in haploidentical transplants. Patients with HLA homozygosity at all loci (HLA-A, B, C, DRB1, and DQB1) undergoing haploidentical transplant is a rare scenario that results in zero mismatches in the graft-versus-host (GvH) direction and 2-5 mismatches in the host-versus-graft (HvG) direction depending on the donor haplotype. This results in a heavily skewed vector of HLA mismatch with unopposed allo-reactivity in the HvG direction. We reviewed our haploidentical transplant database for patients who were homozygous at all five loci and studied their outcomes. Seventy-one patients underwent haploidentical transplant at our center for malignant indications between July 1, 2010, and June 30, 2022. All but one patient received PTCy-based graft-versus-host disease (GvHD) prophylaxis. Of these 71 patients, two were homozygous at all five loci, and both patients developed graft rejection (100%). This was significantly higher than the risk of rejection in the remaining 69 patients where 5/69 (7.2%) had rejection (