Background: The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. Levels of serum ferritin concentration and transferrin saturation, two surrogate markers of iron stores, are used to guide iron replacement therapy. Most First Nation Australians of the Northern Territory with end-stage kidney disease (ESKD) have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. Aim: To assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation. Methods: Using a prospective open-label blinded endpoint randomised controlled trial design, we aim to enrol 576 participants on maintenance haemodialysis with high ferritin (> 700 μg/L and ≤ 2000 μg/L) and low transferrin saturation (< 40%), from renal units across the Northern Territory, to receive intravenous iron polymaltose 400 mg monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700μg/L or when clinically indicated. Conclusion: The INFERR clinical trial will address significant uncertainty regarding the lack of evidence about the safety and efficacy of iron therapy in First Nations Australians with ESKD, who have hyperferritinaemia and evidence of iron deficiency.