Context: Point-of-care glucose meters are an integral part in the assessment of patients with altered mental status. For this reason, glucose meters are checked for interference from commonly encountered substances, including acetaminophen. The Nova StatStrip® glucose meter has previously been reported to be resistant to interference. We report a case of a very high acetaminophen concentration causing interference with this point-of-care glucose meter.Case report: A 25-year-old female presented after an overdose of acetaminophen and diphenhydramine combination product. Patient was minimally responsive, so a point-of-care glucose check was attempted using the Nova StatStrip® glucose meter. Five different meters were attempted, and each showed an error message. Laboratory analysis using Beckman Coulter® Unicel DxC 800 revealed a glucose of 180 mg/dL and an acetaminophen concentration of 465 mg/L. Serum spiked with acetaminophen at different concentrations revealed interference with the Nova StatStrip® glucose meter at a concentration of 399 mg/L and above. To our knowledge, this interference with the Nova StatStrip® glucose meter has not been reported in the medical literature.Conclusion: Very high levels of acetaminophen can interfere with point-of-care glucose meters, even those that have previously been reported to be robust such as the Nova StatStrip® glucose meter. Clinicians should be aware of this possible interference when treating patients with acetaminophen overdose.