The present study was undertaken to define the umbilical cord plasma concentrations of cholesterol throughout human gestation. Mixed arterial and venous cord plasma samples obtained from abortuses of women undergoing elective abortion or from infants of women who underwent spontaneous premature vaginal delivery, and from infants of women who delivered vaginally at term were assayed for cholesterol by a micro-enzymatic method. No cases that involved any maternal or fetal complications (other than prematurity) were included in this study. Early in gestation (10-16 weeks post-conception), the total cholesterol level in cord plasma was 85.4 +/- 30.7 mg/dl (mean +/- SD), N = 68, with the cholesterol levels in some samples falling within the range of those of adults. Between 16.5 and 20 weeks post-conception, the umbilical cord plasma cholesterol level declined to 39.9 +/- 21.0 mg/dl, n = 19 (P less than 0.001). The cholesterol concentration in umbilical cord plasma then rose to 67.8 +/- 24.0 mg/dl, n = 17 (P less than 0.01) between 26.5 and 32 weeks of gestation. Thereafter, a second decline in the umbilical cord plasma cholesterol level occurred, with the values at 32.5-36 weeks being 58.4 +/- 13.6 mg/dl (n = 16), and at 36.5 to 40 weeks post-conception (term) being 51.4 +/- 11.5 mg/dl, n = 44 (P less than 0.01 vs. 26.5-32 wks). We suggest that the observed changes in fetal cholesterol levels could be related to alterations during development in the rates of lipoprotein-cholesterol biosynthesis and subsequent clearance from plasma by the fetal adrenals wherein cholesterol is used as substrate for steroid biosynthesis.