INTRODUCTION: Anemia is one of the most common complications of chronic kidney disease (CKD). As a result of the side effects of high doses of recombinant human erythropoietin (rhEPO) and the differences in the standard dose of the injectable iron, this study aimed to evaluate the effect of high and low intravenous iron supplementation on hematinic parameters and EPO requirements in patients under hemodialysis. METHODS: This multicenter, randomized, double-blind clinical trial was conducted on 60 patients with CKD admitted to Sina and 29 Bahman hospitals in Tabriz, Iran in 2019-2020 to undergo hemodialysis. In the two studied groups, low (100 mg/week) and high (400 mg/week) doses of iron were administered and subjects were followed up for 6 months. The incidence of acute myocardial ischemia, stroke, and mortality during 6 months was recorded. RESULTS: The required rhEPO dosage (mg/week) to maintain hemoglobin levels between 10 and 12 g/dL in the high-dose iron group was significantly decreased during the follow-up period (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.028). Transferrin saturation (TSAT) index had a significant upward trend after iron injection and significant correlations with the serum levels of Fe (r ≥ 0.353, P ≤ 0.007), ferritin (r ≥ 0.315, P ≤ 0.016), and total iron binding capacity (r ≥ 0.219, P < 0.050) during the follow-up period in the studied groups. CONCLUSION: High-dose intravenous iron (400 mg/week) can reduce the mean dose of rhEPO requirements and increase the TSAT index over a period of 6 months in hemodialysis patients. High-dose IV iron administration can decrease cardiovascular events in hemodialysis patients with iron deficiency anemia.