This study examined changes in the natriuretic hormone system in five infants with congestive heart failure (CHF) due to intracardiac left-to-right shunting who were exposed to cardiopulmonary bypass (CPB) during surgical repair. Plasma concentrations of three hormones [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and dendroaspis natriuretic peptide (DNP)] and their secondary messenger, guanosine 3′, 5′-monophosphate (cGMP), were measured, and the biological activity of the system was quantified. At baseline, BNP and DNP concentrations were normal in our patients, a finding that is strikingly different from that of adult CHF patients, whereas ANP concentrations were elevated. Following CPB, ANP concentrations decreased (median, 175 vs 44 pg/ml; p = 0.043) and BNP concentrations increased (median, 25 vs 66 pg/ml; p = 0.043), whereas DNP concentrations did not change. Following modified ultrafiltration, BNP concentrations increased (p = 0.043), but other natriuretic peptide concentrations did not change. The calculated biological activity of the natriuretic hormone system decreased following CPB [molar ratio, cGMP / (ANP + BNP + DNP); median, 213 vs 127; p = 0.043)]. Additional studies are needed to expand on these findings and identify patients with other types of congenital heart disease who have perioperative disturbances in the natriuretic hormone system and thus might benefit from pharmacologic intervention.