Abstract Background and Aims Epitope and antibody diversity allows Bw4+ or Bw6+ patients to produce antibodies to Bw4 or Bw6 epitopes without breaking self-tolerance. This study assessed the prevalence of mismatched Bw4/6 or missing donor Bw6 allele in kidney transplant (KT) recipients with early acute rejection and its relation to patients and graft outcomes. Method A retrospective study included 40 live-related KT recipients divided into 2 equal groups. Group A: 20 KT recipients with early acute rejection in 1st 3 months post-KT and group B: 20 KT recipients with no rejection. Bw4/6 mismatches or missing donor Bw6 were examined in all patients with an assessment of the type of rejection, patients, and graft outcomes. Results The prevalence of Bw4/6 mismatch or missing donor Bw6 allele in patients with early acute rejection was 70% (14 patients). Bw4/6 mismatch represented 25% (5 patients) while missing donor Bw6 allele was 45% (9 patients) while the prevalence of Bw4/6 mismatch or missing donor in patients with no rejection was 10% (2 patients) with significant p-value (0.0001). The analysis of demographic data of Bw4/6 mismatch or missing donor Bw6 allele in patients with rejection (N=14) (Fig. 1); mean age was 27.92 years, 71.4% were males (10 patients), panel reactive antibodies (PRA) was positive in 7.1% (1 patient), Donor specific antibodies (DSA) and complement-dependent cytotoxicity (CDC) cross-match were negative in all patients. The most common type of rejection in these patients was acute antibody-mediated rejection (ABMR) 71.4% (10 patients). Patients and graft outcomes; mean serum creatinine after treatment of rejection was 2.16 mg/dl, mortality was 14.3% (2 patients) with graft loss, and survival with functioning graft was 85.7% (12 patients). Conclusion Bw4/6 mismatch or missing donor Bw6 allele is a risk of early acute rejection in PRA-negative kidney transplant recipients and is linked to negative patients and graft outcomes.