Loss of blood associated with hemodialysis procedures and laboratory testing, together with impaired iron absorption due to elevation of hepcidin, invariably cause iron deficiency in end-stage renal disease patients. For this reason, nearly all ESRD patients require intravenous iron to replete iron stores. Unfortunately, intravenously administered iron is often used routinely with inadequate attention to the body iron stores or severity of systemic inflammation. This has led to an epidemic of iron overload in the ESRD population. Only a minute amount (3-4 mg) of the total body iron (3-4 g in an adult man) resides in the plasma bound to transferrin, which serves as a safe vehicle for iron transport in the circulation. IV iron products are generally administered as bolus injections of 100 to 1000 mg, which far exceeds the available pool of free transferrin and represents a huge quantity compared to the intestinal iron absorption of 1 to 2 mg/day in the course of 3 to 4 meals. Administration of these products results in an increased plasma level of catalytically active non-transferrin bound iron and the rise in the biomarkers of oxidative stress and inflammation. IV iron bypasses the biological safeguards for the transport and handling of iron and helps to intensify chronic kidney disease-associated oxidative stress and inflammation. As briefly described in this review, indiscriminate use of IV iron can accelerate cardiovascular disease, promote microbial infections, aggravate viral hepatitis, and worsen diabetes and diabetic complications in such patients. For these reasons IV iron should be used judiciously in this vulnerable population.