A sensitive isotopic assay was employed to follow the changes in plasma histaminase activity during pregnancy in patients who become pregnant following spontaneous and induced ovulation. Values in nonpregnant women ranged from 0.2 to 2.7 pmoles of histamine deaminated per milliliter of plasma per hour. In pregnant women, plasma histaminase activity began to increase 9 to 28 days following the presumed day of ovulation and then rose exponentially with a doubling time of 4 to 5 days. Peak values, 1,500 pmoles per milliliter per hour, were reached during the third trimester of pregnancy. The data suggested that the increase in histaminase activity actually started at about the same time in all patients, although the early rise in enzyme activity was not apparent in women who had high histaminase activity before pregnancy. Plasma histaminase did not rise in patients with spontaneous abortion, blighted ovum with hydatidiform degeneration, or choriocarcinoma. The high levels of chorionic gonadotropin and low levels of histaminase activity seen in patients with trophoblastic neoplasia suggest that these tests may be of value in the diagnosis of trophoblastic neoplasia early in pregnancy.