Williams syndrome (WS) is a neurodevelopmental genetic disorder associated with high rates of anxiety and social issues. We examined diurnal cortisol, a biomarker of the stress response, in adults with WS in novel and familiar settings, and compared these profiles to typically developing (TD) adults. WS and TD participants had similar profiles in a familiar setting, while participants with WS had elevated cortisol late in the day in the novel setting when social demands were higher. The cortisol awakening response in WS was associated with parent-reported levels of somatic complaints and social difficulties. Results suggest that adults with WS have a typical diurnal cortisol profile that may be sensitive to social and activity transitions throughout the day.