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Ankle sprain has been studied in athletic cohorts, but little is known of its epidemiology in the general population. A longitudinal, prospective epidemiological database was used to determine the incidence and demographic risk factors for ankle sprains presenting to emergency departments in the United States. It was our hypothesis that ankle sprain is influenced by sex, race, age, and involvement in athletics.The National Electronic Injury Surveillance System (NEISS) was queried for all ankle sprain injuries presenting to emergency departments between 2002 and 2006. Incidence rate ratios were then calculated with respect to age, sex, and race.During the study period, an estimated 3,140,132 ankle sprains occurred among an at-risk population of 1,461,379,599 person-years for an incidence rate of 2.15 per 1000 person-years in the United States. The peak incidence of ankle sprain occurred between fifteen and nineteen years of age (7.2 per 1000 person-years). Males, compared with females, did not demonstrate an overall increased incidence rate ratio for ankle sprain (incidence rate ratio, 1.04; 95% confidence interval, 1.00 to 1.09). However, males between fifteen and twenty-four years old had a substantially higher incidence of ankle sprain than their female counterparts (incidence rate ratio, 1.53; 95% confidence interval, 1.41 to 1.66), whereas females over thirty years old had a higher incidence compared with their male counterparts (incidence rate ratio, 2.03; 95% confidence interval, 1.65 to 2.65). Compared with the Hispanic race, the black and white races were associated with substantially higher rates of ankle sprain (incidence rate ratio, 3.55 [95% confidence interval, 1.01 to 6.09] and 2.49 [95% confidence interval, 1.01 to 3.97], respectively). Nearly half of all ankle sprains (49.3%) occurred during athletic activity, with basketball (41.1%), football (9.3%), and soccer (7.9%) being associated with the highest percentage of ankle sprains during athletics.An age of ten to nineteen years old is associated with higher rates of ankle sprain. Males between fifteen and twenty-four years old have higher rates of ankle sprain than their female counterparts, whereas females over thirty years old have higher rates than their male counterparts. Half of all ankle sprains occur during athletic activity.Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.