Children with single ventricle physiology have increased ventricular work and are at greater risk of developing heart failure than other children with congenital heart disease. However, the diagnosis of heart failure is difficult because few objective measures have been validated for this cohort. Plasma proteins have been identified as biomarkers of heart failure in adults with structurally normal hearts. However, whether these correlate similarly with heart failure in children with single ventricle physiology is unknown, because the etiology of adult heart failure is typically ischemic heart disease, but heart failure in these children is presumed to be due to primary myocardial dysfunction. We conducted a single-site, cross-sectional observational study of young, single-ventricle patients. Clinical heart failure was defined as a Ross score >2. The association of several candidate biomarkers with heart failure was assessed using logistic regression analysis and receiver operating characteristic curves. Of the 29 included children, 9 (31%) were in clinical heart failure. A doubling of plasma B-type natriuretic peptide was associated with an odds ratio for heart failure of 2.17. The area under the receiver operating characteristic curve was 80.3%. A threshold value of > or =30 pg/ml showed both sensitivity and specificity for heart failure. Three other candidate biomarkers were not associated with clinical heart failure in this sample. In conclusion, plasma B-type natriuretic peptide is a sensitive biomarker for clinical heart failure in young children with single-ventricle heart disease. The use of this plasma biomarker might facilitate detection of heart failure in these complex patients.