Disability became increasingly common with age, and crude rates of disability were rising around the globe. The aim of this study was to investigate the association between calf circumference (CC) and disability in the U.S. elderly population. From the 1999-2006 National Health and Nutrition Examination Survey, a total of 4,245 participants with an age range of 60-84 years were included. Disability was defined as the total number of difficulties within the following 5 major domains of disability, such as activities of daily living (ADL), instrumental ADL, general physical activities, lower extremity mobility, and leisure and social activities. The association between CC and disability was investigated through the regression model adjusted for multiple covariates. According to the fully adjusted model regarding disability, the β coefficients for each quartile of increasing CC were -0.041 for quartile 2 (P = 0.096), -0.060 for quartile 3 (P = 0.027), and -0.073 for quartile 4 (P = 0.026) respectively, compared with lowest quartile. There was a negative association between CC and disability among the elderly population. Calf circumference may be a novel risk assessment for disability of elderly people.