To investigate whether atrial natriuretic peptide is present in the human fetal circulation and changes in response to fetal blood volume expansion, the concentration of plasma atrial natriuretic peptide was measured by radioimmunoassay in samples obtained by cordocentesis. Twenty-four patients referred for intravascular blood transfusion because of red cell isoimmunization at 21 to 35 weeks' gestation were studied. Plasma atrial natriuretic peptide concentrations in fetal blood (median, 8.0 pmol/L; range, 1 to 27.3) were significantly higher than those of 25 young 18- to 32-year-old adult control subjects (median, 4.5 pmol/L; range, 1 to 11.3, p less than 0.002 but similar to those found in the umbilical cord blood of 10 normal neonates immediately after delivery (median, 7.35 pmol/L; range, 2.7 to 15.5). In seven patients in whom fetal and maternal plasma atrial natriuretic peptide was measured simultaneously, all fetal concentrations were higher (p less than 0.01). The concentration of fetal atrial natriuretic peptide before and immediately after blood transfusion (n = 12) rose significantly (p less than 0.05), and the rise correlated positively with the transfusion rate (p less than 0.05). We conclude that atrial natriuretic peptide is present in plasma of the human fetus as early as 21 weeks' gestation and that its concentration increases promptly in response to vascular volume expansion. These findings suggest that atrial natriuretic peptide may play a role in fetal volume homeostasis.