In adults without congenital heart disease, B-type natriuretic peptide (BNP) has been shown to be a very sensitive and specific marker of heart failure. The utility of BNP as a marker of clinical heart failure in children with a ventricular septal defect (VSD) has yet to be determined. A prospective, observational study evaluated BNP levels and other measures of heart failure. Eligible patients were <2 years old, scheduled to undergo surgical repair of a VSD, and without other significant structural heart disease. Data collected before and after surgical repair included echocardiographic measurements, electrocardiographic (ECG) findings, Ross score, BNP measurements, and weight gain. A total of 21 patients were enrolled and 14 patients had complete postoperative follow-up data. For patients with complete data, mean BNP decreased by 94 pg/ml (118 pre vs. 24 post; paired t-test, p = 0.041), mean left ventricular end-diastolic dimension z-score decreased by 1.75 (+0.86 vs. −0.89; paired t-test, p = 0.013), mean weight z-score change per month increased by 0.35 (−0.25 vs. +0.10; Wilcoxon test, p = 0.013), and the incidence of biventricular hypertrophy on ECG decreased (46% vs. 0%; McNemar test, p = 0.031). The change in BNP showed a trend toward a negative correlation with weight z-score change per month (r = −0.531, p = 0.075). In conclusion, BNP, along with other measures of heart failure, decreased following VSD repair, and the change in BNP was most closely correlated with improved weight gain.