ABSTRACT: First trimester (10–12 weeks gestation) human decidua contains small lymphocytic suppressor cells that release 22 and 43 kd soluble suppressor factors blocking the action of interleukin 2. Luteal phase endometrium, in contrast, contains large suppressor cells that do not release soluble immunosuppressive factors. However, if luteal phase endometrium from days 24 to 25 of the menstrual cycle is incubated with placental syncytiotrophoblast membrane vesicles, suppressor factors having the same molecular weight as those found in end of first‐trimester pregnancy decidua are released into the supernatant. This generation of soluble suppressor activity is dependent on cells similar in size to the small lymphocytic suppressor cell population. When uterine decidua is obtained from women with tubal ectopic pregnancy (early in the first trimester), the decidual tissue releases soluble immunosuppressive factors with a 100–135 kd molecular mass and the suppressor cells are large rather than small in size. Supernatant conditioned by trophoblast dissected from ectopic implants was able to interact with large cells in luteal phase endometrium to generate additional soluble suppressor activity. A model is proposed wherein fetal trophoblast activates two suppressor cell populations (large and small) in endometrium via soluble long‐range inducer and by direct contact with trophoblast membrane. The potential role of trophoblast‐dependent suppressor cells in preventing rejection of the conceptus leading to occult or clinical abortion is discussed.