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Background: Renal transplant recipients with donor-specific anti-HLA antibodies are at an increased risk of antibody-mediated rejection (ABMR). Early protocolized renal biopsies may serve as a strategy to improve diagnosis in this patient population., Methods: We evaluated 155 highly sensitized renal transplant recipients with cPRA class I + II >90% pre-transplant from 2015 to 2022. Patients with protocol biopsies within the first 2 weeks post-transplant were included., Results: A total of 122 patients were included in the study. Of these, 13 (10.6%) were diagnosed with very early antibody-mediated rejection (veABMR) within the first 2 weeks post-transplant. This corresponds to 52% (13/25 patients) of all ABMR cases reported during the follow-up of this population. The graft survival rates at 1 and 3 years were significantly lower in patients with veABMR (P < .001) compared with patients without rejection in the early protocol biopsy. In terms of severity, the veABMR cohort exhibited a hazard ratio (HR) of 10.33 (95% confidence interval 3.23-33.06, P < .001) for graft failure. The presence of donor-specific antibodies class II on the day of transplantation and a higher percentage of eplet mismatch (EpMM), particularly EpMM DQA1, correlated with the development of veABMR., Conclusion: Early protocol biopsies play a pivotal role in the early detection of veABMR in high-risk immunological patients. Patients with veABMR face significant risks of graft loss, despite early treatment of rejection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)