Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE: Whether cognition is influenced by arterial stiffness in the absence of vascular disease remains uncertain. OBJECTIVE: To test the hypotheses that indirect measures of arterial stiffness are important predictors of cognitive performance and that this relationship varies depending on the presence of vascular disease. DESIGN, SETTING, AND PARTICIPANTS: Participants included 2573 noninstitutionalized US adults randomly selected from 2 cycles of the National Health and Nutrition Examination Survey (1999-2002). The sample was stratified by groups based on the presence (VASC+) vs the absence (VASC-) of vascular variables negatively associated with cognition to assess the effects of indirect measures of arterial stiffness on cognitive performance. We used logistic regression to obtain odds ratios (ORs) and their 95%CIs. P < .05 was considered statistically significant. MAIN OUTCOMES AND MEASURES: The Digit Symbol Substitution Test score was used as a continuous variable, and the lowest quintile was designated as an indicator of poorer cognitive performance. RESULTS: In the VASC+ group, poorer cognitive performance was more likely with increasing age (OR, 1.12 [95%CI, 1.08-1.17]; P < .001), a sedentary lifestyle (OR, 2.99 [95%CI, 1.62-5.55]; P = .002), and the use of dihydropyridine calcium channel blockers (OR, 9.24 [95%CI, 1.35-63.23]; P = .02). Poorer cognitive performance in the VASC+ group was less likely in women (OR, 0.37 [95%CI, 0.18-0.72]; P = .02), non-Hispanic white individuals (OR, 0.16 [95%CI, 0.09-0.26]; P < .001), those with higher educational attainment (OR, 0.23 [95%CI, 0.14-0.38]; P < .001), those with higher income levels (OR, 0.56 [95%CI, 0.72-0.76]; P < .001), and those who used renin-angiotensin system blockers (OR, 0.24 [95%CI, 0.07-0.79]; P = .02). In the VASC- group, the most important significant predictors of poorer cognitive performance were an ankle brachial index greater than 1.30 (OR, 18.56 [95%CI, 2.94-117.05]; P = .002) and increased blood pressure variability (OR, 3.49 [95%CI, 1.07-11.35]; P = .04). Among participants in the VASC- group who had both of these variables, the prevalence of poorer cognitive performance was greater (β = 16.65; P < .001). CONCLUSIONS AND RELEVANCE: Two indirect measures of arterial stiffness, an ankle brachial index greater than 1.30 and increased blood pressure variability, are associated with poorer cognitive performance among adults 60 years or older without clinical atherosclerotic disease. Among those with vascular disease, factors capable of influencing arterial stiffness, such as exercise and the use of renin-angiotensin system blockers, may be protective against poorer cognitive performance.