OBJECTIVES: We estimated economic burden associated with emergency department (ED) visits and outpatient/ambulatory visits for hypoglycemia for year 2005-2009. METHODS: We analyzed the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Ambulatory Medical Care Survey (NAMCS). The NHAMCS has ED and outpatient department (OPD) components. The unit cost can be estimated from the Medical Expenditure Panel Survey (MEPS) for patients with diabetes (n=1010 in 2005, 1115 in 2006, 1039 in 2007, 1164 in 2008, 1276 in 2009). The annual costs were estimated by the multiplication of the MEPS unit costs and annual NHAMCS and NAMCS health care utilization associated with hypoglycemia. We did not estimate the annual hospitalization costs in NHAMCS OPD and the NAMCS due to no information on length of stay. All costs were adjusted to the U.S. 2009 dollars. RESULTS:  The MEPS unit cost increased from $692 in 2005 to $932 in 2009, the annual expenditure of hypoglycemia ED visits fluctuated between $339 million in 2007 and $400 million in 2006 due to the estimated total hypoglycemia visits declined over those 5 years.  Hospital admissions from emergency department associated with hypoglycemia ED visits was in a declining trend of 2005-2009 and the lowest in 2009 (n=71,751). Consequently, the estimated annual expenditure of hospital admission from ED declined each year from 2005 ($2.90 billion) to 2009 ($1.25 billion).  The expenditure of hypoglycemia visits to ambulatory facilities fluctuated between 0.37 million in 2007 and 1.08 million in 2008, resulting in the estimated annual cost of approximately $80.46 million to $229.03 million, respectively.  CONCLUSIONS: Annual direct medical cost associated with hypoglycemia in the U.S. was $3.49 billion in 2005 and declined to $1.84 billion in 2009. The trend may be attributed to improvements in patient education, glucose monitoring, and new anti-diabetic medications with lower risk for hypoglycemia.