To study the placental transfer and pharmacokinetics of the H1 receptor blocker, diphenhydramine [2-(diphenylmethoxy)-N,N-dimethylethylamine], 100 mg of the drug was administered to four pregnant sheep (122–129 d gestation) by intravenous injection through catheters chronically implanted in the ewe and fetus. Rapid placental transfer occurred, with peak fetal plasma concentrations occurring within 5 min after injection. The fetal-maternal ratio of the area under the plasma concentration versus time curves averaged 0.85, indicating significant fetal exposure to the drug. The average apparent terminal elimination half-life in the ewe (52 min) was not significantly different from that obtained in the fetus (46 min). The maternal total body clearance was 3.6 L.h−1.kg−1, and the volume of distribution at steady state was 3.2 L/kg. In summary, this study demonstrates rapid and extensive placental transfer of diphenhydramine after maternal drug administration. Since placental permeability to lipid-soluble compounds does not differ greatly in different species, it is likely that a similar situation exists in humans.