Background: Previous studies have shown that patients with congenital heart disease (ConHD) report a diminished health-related quality of life. Purpose: This study examines the mechanisms by which ConHD affects health-related quality of life. We hypothesize that (1) the relation between trait anxiety and quality of life is mediated by a negative interpretation bias for heart sensations, specifically in ConHD, and that (2) the relation between trait anxiety, and interpretation bias is mediated by state anxiety. Method: Sixty-six patients with ConHD and 50 healthy participants read a vignette about a person experiencing ambiguous heart-related sensations. Interpretation bias to these sensations was assessed with the Implicit Models of Illness Questionnaire. Participants completed Spielberger trait and state anxiety questionnaires and the physical subscales of a quality-of-life questionnaire. Results: Path-analysis demonstrated that interpretation bias mediated the relation between trait anxiety and daily functioning. However, trait anxiety and interpretation bias were less influential with respect to gross motor functioning. Moreover, state anxiety mediated the relation between trait anxiety and interpretation bias. Conclusion: These results suggest that patients with ConHD who display both elevated levels of trait and state anxiety exhibit the most pronounced negative interpretation bias for heart sensations and in turn diminished daily functioning.