Oxycodone and oxycodone-containing analgesics are often used for the relief of pain. In the presence of renal dysfunction, the half-life of oxycodone and metabolites can be prolonged. We describe the case of a 41-year-old chronic hemodialysis patient who received multiple doses of oxycodone/acetaminophen resulting in accumulation of the medication and consequent lethargy, hypotension and respiratory depression. These adverse effects were reversed with multiple bolus doses of naloxone, followed by a continuous infusion administered for 45 hours. Utilizing the Naranjo probability scale, the patient had a “probable” adverse drug reaction to the oxycodone. Oxycodone should be used with caution in patients with chronic renal failure.