Analgesic nephropathy results from chronic abuse of non-narcotic analgesics, most frequently with the use of phenacetin and mixed analgesic preparations. Renal papillary necrosis and chronic interstitial nephritis with progressive scarring are characteristic of the histopathology of analgesic nephropathy. Typically, papillary necrosis in these patients is bilateral and affects almost all renal papillae. This report describes a case of severe analgesic nephropathy that discriminantly affected a unilateral non-functioning kidney and spared the contralateral normally developed kidney. The patient herein consumed therapeutic doses of acetaminophen and naproxen daily and for several years. We estimated the cumulative doses of acetaminophen and naproxen used by the patient during that period to be approximately 1.0 and 0.4 kg, respectively. The cumulative dose of acetaminophen is at the threshold of doses that were traditionally associated with an increased risk for end-stage kidney failure. Simultaneous intake of both analgesics could have had a synergetic adverse effect on renal function. This case also demonstrates that preexisting renal insufficiency is prerequisite to the development of analgesic nephropathy. Conversely, kidneys with normal function are resistant to the chronic nephrotoxicity associated with habitual analgesic use.