Bacterial invasion of the renal parenchyma, pyelonephritis, is rarely considered as a primary cause of acute renal failure, particularly in adults. We report two cases of acute renal failure occurring in absence of hypotension, urinary tract obstruction, or nephrotoxic medications that are likely the direct consequence of pyelonephritis. The first case involved a 48-year-old HIV-positive woman who presented with 3 days of nonspecific symptoms and was noted to have acute renal failure. Due to unremitting renal dysfunction, a renal biopsy was performed confirming the diagnosis of bacterial pyelonephritis. The second case, a 33-year-old man with HIV disease, presented with fever and was found to have pyelonephritis by urine culture and ultrasonography. These cases represented initial diagnostic dilemmas for the admitting physicians and demonstrate the varied clinical presentations of acute renal failure as a direct consequence of bacterial infiltration of the renal parenchyma.