Studies on full-term human placentas were conducted to determine whether the vasogenic actions of certain agents on perfused placental vasculature are due to histamine release. Compound 48/80 and morphine were selected because they liberate the autacoid via different mechanisms. Initially, a control effluent was collected prior to each drug challenge and again collected throughout the rise and fall in perfusion pressure. The drugs were given alone and in the presence of a 50 mcg dose of histamine free base (HFB) to assess the release of stored histamine and also to serve as a control. Following extraction in n-butanol and recovery in 0.1 N HCl, all effluents were fluoresced with o-phthalaldehyde and assayed for histamine content via spectrophotofluorometry. A baseline histamine level was discovered in the majority of placental effluents collected prior to the administration of any agent. No significant increases above this initial level occurred following treatment with compound 48/80 alone. However, small but significantly elevated amounts of histamine appeared in the placental effluent when compound 48/80 was given 10 minutes after the initial 50 mcg dose of HFB. This agent also caused a slight increase in placental perfusion pressure after each administration. Results obtained with morphine do not appear to support the hypothesis that significant amounts of histamine are released by this agent in the perfused human placenta.