Human pre-implantation stage embryos cultured in vitro spontaneously secreted a factor capable of inducing histamine-release from human blood basophils. The embryo-derived histamine-releasing factor (EHRF) has been isolated from the culture medium by means of heparin-Sepharose affinity chromatography. The factor bound to the column and was then eluted by increasing the buffer molarity to 1.5 M NaCl. EHRF was detected using an enzymatic-isotopic microassay and sensitized basophils known to undergo release with anti-IgE. The EHRF-induced histamine-release was calcium and temperature dependent and the relatively slow kinetics (10 min) were similar to those obtained with anti-IgE. EHRF caused the release of a substantial amount of histamine (48%, n = 18) in a dose-dependent manner. The equivalent fraction isolated from medium containing unfertilized oocytes gave less than 10% of histamine-release using the same source of basophils, suggesting that EHRF was secreted after fertilization. EHRF was very stable since it was resistant to boiling, lyophilization, and to several freeze and thaw treatments. The histamine-releasing activity induced by EHRF was measured in vitro also by means of purified leukocytes containing sensitized basophils. EHRF could represent a message sent by the embryo to the mother to induce histamine release at the time of implantation.