BACKGROUND: Anaemia is prevalent after intensive care unit (ICU) discharge as a consequence of factors such as blood sampling, concurrent inflammation affecting erythropoiesis, and the use of restrictive ICU red blood cell (RBC) transfusion practice during inpatient stay. ICU survivors experience poor health-related quality of life (HRQoL). Prevalent symptoms include fatigue and weakness, to which anaemia may contribute. There are no trials exploring the effectiveness of treating anaemia with RBC transfusions post-ICU discharge. METHODS AND ANALYSIS: The ABC post-ICU trial is a multicentre prospective, parallel group, randomised trial, with embedded moderation and mediation analysis. Participants are adult ICU survivors with anaemia (haemoglobin (Hb) ⩽94 g/L) fit for ICU discharge. Patients are randomised to usual care (default Hb transfusion trigger <70 g/L, target 70-90 g/L) or single-unit RBC transfusions to achieve Hb range 100-120 g/L. The intervention is from randomisation to hospital discharge. Primary outcome is the physical component summary score (PCS) of the 36-item short form (SF-36) health survey, which measures HRQoL, assessed 90 days post-randomisation. Secondary outcomes at 90 days include: hospital length of stay, mortality, fatigue score, activities of daily living, and Mental Component Scale score (MCS) SF-36. Outcomes are also measured at 30 and 180 days. Safety outcomes include: new infections, transfusion-related adverse events, and major adverse cardiac events. Analysis includes a moderation analysis based on baseline recalled PCS SF-36, comorbidity burden, mobility, and systemic inflammation (C-reactive protein (CRP) concentration). A mediation analysis based on 30 days blood samples will explore whether anaemia severity (Hb) or persisting inflammation (CRP) mediates intervention effects. A health-economic analysis over 180 days will be conducted. The sample size is 346, providing 90% power to detect a difference in PCS SF-36 of 5 points, assuming >70% completed SF-36 follow-up. CLINICALTRIALSGOV: NCT04591574.