Serial measurements were made of the concentrations of maternal serum human placcntal lactogen (hPL) (300 determinations), estriol (E3) (460 determinations), and estetrol (E4) (275 determinations) in normal human pregnancy during the third trimester period. Simultaneous determinations of serum hPL, E3, and E4 were also made sequentially on blood samples from 6 diabetic and 5 toxemic pregnant women to ascertain the relative usefulness of these parameters as indicators of fetal welfare. In uncomplicated diabetic patients controlled with insulin, all parameters increased with gestational age. In three pregnancies complicated by severe toxemia in which fetal distress progressed to intrauterinc fetal death, both serum E3 and E4 levels decreased progressively, but E4 concentration started to decrease at least 1 day earlier than E3 prior to fetal death. In other women, the E3 levels appeared to drop or decrease significantly whereas the E3 levels remained almost unchanged. Daily hPL levels remained low in chronic fetal distress and, therefore, appeared to be of minimal value for predicting either intrauterine death or acute fetal distress. Therefore, serum E4 measurement seems to provide a more sensitive and reliable indicator of fetal morbidity than the measurement of serum E3 during toxemic pregnancies.