Aims: Advances in medical treatment have resulted in increased life expectancy in congenital heart disease. Consequently, the focus of management has shifted from reducing mortality to reducing long-term morbidity with the goal of improving quality of life. A predictor of quality of life might be N-terminal pro-brain natriuretic peptide, a well-established marker for heart failure. We aimed to determine the association between N-terminal pro-brain natriuretic peptide and quality of life in patients with congenital heart disease. Methods: We collected blood samples from consecutive patients who were initially operated between 1968 and 1980 (47.8% women; mean age 40.2±5.4 years). The 36-item Short-Form Health Survey was completed to assess subjective health status as a measure of quality of life. Analysis was performed for the entire group and for subgroups defined as simple versus complex congenital heart diseases. Median N-terminal pro-brain natriuretic peptide level was 15.2 pmol/L (overall range 1.3–299.3 pmol/L). N-terminal pro-brain natriuretic peptide levels were associated with the subdomain physical functioning (β=−0.074, p=0.031). This association remained significant after adjustment for age and sex (β=−0.071, p=0.038) and after adjustment for age, sex, body mass index, left ventricular function, and renal function (β=−0.069, p=0.048). In complex congenital heart disease, the association between N-terminal pro-brain natriuretic peptide and physical functioning remained significant in multivariable analysis (β=−0.076, p=0.046). No associations were found in the simple congenital heart disease group or on the other health status subdomains. Conclusion: In adults operated for congenital heart disease, N-terminal pro-brain natriuretic peptide is associated with the subdomain physical, primarily in the complex subgroup.