Summary Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry‐based matched‐pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair‐matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T‐cell depletion. Eighty‐nine pairs were identified (median follow‐up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high‐risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high‐risk AML.