OBJECTIVES: The purpose of this study was to estimate the morbidity cost of Unintentional Non-fire (UNFR) Carbon Monoxide (CO) poisoning, including medical costs and non-health-sector costs. We also compared the costs and benefits of installing CO detectors in residences. METHODS:  We used 2009–2013 charges and cost data from the National Inpatient Sample (NIS), Nationwide Emergency Department Sample (NEDS) of Healthcare Cost and Utilization Project (HCUP), and Truven^© Health MarketScan Commercial Claims and Encounters and Medicare Supplemental data. We directly measured the morbidity cost as the summation of medical and non-health-sector costs from different health care services using micro-costing method. Benefit of installing CO detector was estimated by summing up the morbidity cost and mortality cost (value of life). All the costs were converted into 2013 dollar. RESULTS:  Total annual medical cost ranged from $33.6 to $38.1 million. Hospitalizations, outpatient hospital visits, and emergency department (ED) visits accounted for approximately two thirds of the medical cost. Annual non-health-sector costs varied from $3.7 to almost $5 million, approximately 80% of which were related to time spent on hospitalization and ED visits. Total morbidity cost (resulting from medical cost and non-health-sector cost) was between $37.3 and $43.1 million annually. Total annual benefit of installing CO detectors, including 60% of the morbidity cost averted and 50% of the mortality cost averted, ranged from $1.6 billion to $2.2 billion. Therefore, the benefit-to-cost ratio of installing CO detectors in residences can be as high as 7.9 to 1 in the least expensive case. CONCLUSIONS:  UNFR CO poisoning causes significant economic burden in the U.S. The benefit of using CO detectors in homes can considerably exceed the cost of installation. Public health programs should use these findings to promote broad installation of CO detectors in homes.