An abnormally high ankle-brachial index (ABI) is associated with increased all-cause and cardiovascular mortality. The relation of obesity to incident high ABI has not been characterized. The aim of this study was to investigate the hypothesis that increased obesity—quantified by body weight, body mass index, waist circumference, and waist-to-hip-ratio—is positively associated with a high ABI (≥1.3) and with mean ABI increases over a 4-year follow-up. Prevalence and incidence ratios for a high ABI were obtained for 6,540 and 5,045 participants, respectively, in the Multi-Ethnic Study of Atherosclerosis (MESA), using log-binomial regression models adjusted for demographic, cardiovascular, and inflammatory and novel risk factors. Linear regression was used to analyze mean ABI change. The prevalence and incidence of a high ABI were significantly higher for the highest compared to the lowest quartile of every baseline measure of obesity, with weight and body mass index demonstrating the highest incidence ratios (2.7 and 2.4, respectively). All prevalence and incidence ratios were positive and graded across obesity quartiles and were persistent in the subpopulation without diabetes. In those with normal baseline ABI values, 1 MESA standard deviation increase in every baseline measure of obesity was associated with significant increases in mean ABI values. In conclusion, independent, positive, and graded associations of increasing obesity with prevalent and incident high ABI and with mean increases in ABI values over time were found. Weight and body mass index seemed to be at least as strongly, if not more strongly, associated with a high ABI than were measures of abdominal obesity.