Megalocytic interstitial nephritis is rare and primarily affects the cortex in an otherwise normal kidney. We recently encountered a patient with Escherichia coli bacteremia and oliguric acute renal failure who died of gram-negative septicemia. At autopsy, this patient's kidneys displayed typical features of megalocytic interstitial nephritis. We were able to perform special stains suggesting that the histiocytic interstitial cells originated from infiltrating macrophages. Our patient illustrates that macrophage proliferation can result in interstitial inflammation sufficiently severe to cause anuric acute renal failure.