The present study investigated how the Big Five personality traits were related to quality of life and perceived health in adolescents with congenital heart disease (CHD). Adolescents with CHD were selected from the database of pediatric and congenital cardiology of the University Hospitals Leuven. A total of 366 adolescents (15-20 years) participated; 364 were matched on sex and age with community controls. Adolescents’ personality was assessed using the Quick Big Five, quality of life was measured using a Linear Analogue Scale, and several domains of perceived health were assessed using the Pediatric Quality of Life Inventory. Adolescents with CHD displayed similar Big Five levels as controls, except for a lower score on Extraversion. Whereas disease-specific domains of perceived health were mainly related to Emotional Stability, several traits contributed to patients’ quality of life and generic perceived health. Hence, the present findings demonstrate that the Big Five is a valuable framework for examining linkages between personality and disease adaptation in chronic disease populations. Moreover, these findings underscore the importance of examining patients’ personality to shed light on their daily functioning. Future research should explore potential mechanisms detailing how personality influences disease adaptation over time in these patients.