Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral manifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was measured by a 1-hour access to food four times throughout the study and quantified with a visual analogue scale. Topiramate did not significantly change calories consumed, Body Mass Index, or increase self-reported appetite. In addition, there were no significant changes in compulsions. Surprisingly, topiramate treatment resulted in a clinically significant improvement in the self-injury (i.e., skin-picking) that is characteristic of this syndrome. Potential benefits of topiramate for self-injury should be evaluated further in controlled trials.