Clinical and molecular analyses of Costello syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello syndrome. The survey consisted of the Costello syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello syndrome (age 16–34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P < 0.008). The CSQoL:Caregiver total scores appear negatively correlated with total number of medical issues (r = −0.549; P = 0.065). No association was found between the CSQoL:Self scores and total number of medical issues (r = −0.107; P = 0.769). Four impediments to QoL for individuals with Costello syndrome were identified: relationships outside of their immediate circle of family and friends, lack of independence, male gender, and the presence of major medical issues. This information may be useful to the families and health care professionals of adults with Costello syndrome. As a measurable characteristic, QoL may have utility as a metric in future therapeutic trials. © 2009 Wiley-Liss, Inc.