Background: We previously showed cyclic guanosine 3',5'-monophosphate (cGMP) levels increase with fetal cardiac bypass despite derangements in the placental nitric oxide pathway. The natriuretic peptides, atrial (ANP), brain (BNP), and c-type (CNP), are common indicators of cardiac distress, and an alternative pathway for cGMP generation. We hypothesized that these natriuretic peptides may account for the paradoxic rise in cGMP seen with fetal bypass. Methods: Six ovine fetuses, 106 to 118 days' gestation, underwent cardiac bypass for 30 minutes and were followed for 120 minutes after bypass. Fetal plasma samples were collected before bypass, during bypass, and 30 and 120 minutes after bypass for natriuretic peptide analysis. Results were compared with 6 sham bypass fetuses and cGMP values from another 14 bypass fetuses (to avoid confounding effects of excess blood sampling). Fetal hemodynamics and metabolics were correlated to ANP, BNP, and CNP values. Statistical analysis was by analysis of variance, Student′s t test, and best-fit correlations, with significance set at p = 0.05 or less. Results: The ANP, BNP, and CNP increased with fetal bypass (674 ± 133 pg/mL, 151 ± 52 pg/mL, and 295 ± 45 pg/mL, respectively), remaining elevated after bypass, whereas sham concentrations remained stable at pre-bypass levels. Changes in ANP, BNP, and CNP positively correlated with rising cGMP. There was positive correlation between ANP and CNP and rising fetal lactate levels, but not to other physiologic parameters associated with placental dysfunction. Conclusions: There is a substantial rise in natriuretic peptides seen with fetal bypass, likely in part a reflection of myocardial dysfunction. Further, the natriuretic peptide pathway may account for the paradoxic rise in cGMP seen with fetal bypass.