Individuals with Prader-Willi syndrome (PWS) are often overweight or obese because of their delayed satiety response. Three individuals with PWS participated in a long-term, multicomponent mindfulness-based health wellness program to reduce their obesity by changing their lifestyles. The components included (a) physical exercise, (b) food awareness, (c) mindful eating to manage rapid eating, (d) visualizing and labeling hunger, and (e) a mindfulness procedure used as a self-control strategy against temptation to eat between meals. The program was implemented within a changing criterion design. All 3 individuals reached their desired body weights, enhanced their lifestyles, and maintained their desired body weights during the 3-year maintenance period. This study suggests that mindfulness-based health wellness programs may be effective in producing sustained lifestyle changes in individuals who are obese, including those with a biological predilection for excessive eating due to delayed satiety response. (Contains 3 figures and 1 table.)