© 2019, Society of General Internal Medicine (This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply). Background: Functional limitations may be more common in middle-aged adults than previously recognized. However, there are few published data on the prevalence of activity limitations, and their association with multimorbidity, among adults 50 to 64 years old. Objective: To describe the prevalence of activity limitations and the association with multimorbidity in middle-aged adults. Design: Cross-sectional analysis of US population-based National Health and Nutrition Examination Survey (NHANES) 2011–2016. Participants: The total number of community-dwelling NHANES participants aged 50–64 years old is 4217. Main Measures: Chronic conditions included hypertension, high cholesterol, diabetes mellitus, obesity, chronic kidney disease, cancer, stroke, coronary heart disease, heart failure, chronic obstructive pulmonary disease/asthma, arthritis, and depression. Activity limitations were defined as any difficulty within each of four International Classification of Functioning (ICF) domains: functional limitations (kneeling, carrying, standing, sitting, reaching, grasping, pulling), mobility (walking ¼ mile, climbing 10 steps), basic activities of daily living (BADLs; walking, transferring, eating, dressing), and instrumental activities of daily living (IADLs; finances, chores, cooking). We calculated prevalence ratios for activity limitations using generalized estimating equations. Key Results: The prevalence of functional limitations, mobility limitations, BADL difficulty, and IADL difficulty was 34%, 11%, 15%, and 17%, respectively. Seventy-two percent of participants had two or more chronic conditions; 23% had two, 18% had three, 15% had four, and 16% had five or more. Multivariable adjusted prevalence ratios (95% CI) for functional limitations among those with 2, 3, 4, and 5 or more chronic conditions, compared with 0–1 conditions, were 1.94 (1.43–2.63), 2.50 (1.93–3.23), 3.26 (2.48–4.27), and 4.54 (3.48–5.93), respectively (p trend < 0.001). Larger prevalence ratios at a higher number of chronic conditions were present for mobility limitations, BADL difficulty, and IADL difficulty. Conclusions: Problems with function are not limited to older adults and multimorbidity may be helpful for identifying middle-aged adults with a high prevalence of activity limitations.