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Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure., Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients., Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection., Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy., Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34)., Competing Interests: DB declares consulting fees and speaker honoraria from Hansa Biopharma. RT declares membership of ESOT Education Committee (2018–2021) (expenses reimbursed). PM declares research funding from NIHR. AD declares research funding from the 10.13039/501100007155Medical Research Council, consulting fees (paid to KCL) from Hansa Biopharma, Verici Diagnostics, UCB Pharma and Quell Therapeutics, Membership of the Herperis Faculty 2019, 2021 and 2022 (expenses reimbursed), Membership of the UK Organ donation and transplantation research network executive since 2020 (unpaid), Membership of the EME funding Committee (2014–2019) and the EME funding committee subgroup (2018–2019) (both unpaid). The remaining authors declare no conflicts of interest., (© 2023 The Authors.)