Prostaglandin F2 alpha (PGF2 alpha) is capable of inducing a decidual cell reaction (DCR) in the hormonally prepared rat. In the present work indomethacin, a PG synthetase inhibitor, was used to determine whether PGF2 alpha is involved in the DCR induced by artificial stimulation of the endometrium. Thirty-seven animals were oophorectomized and subsequently given daily injections of progesterone for 6 days and one injection of estradiol 17 beta on the fourth day. Later on the fourth day, one of several experimental maneuvers was carried out on the right uterine horn of each animal; these included: 1) introduction of phosphate-buffered saline (PBS) twice into the uterus, 2) intrauterine injection of PGF2 alpha with no subsequent application or manipulation, 3) intrauterine injection of indomethacin followed by subsequent injection of PGF2 alpha, 4) intrauterine injection of indomethacin with subsequent artificial stimulation (scratch), 5) intrauterine injection of PBS with subsequent scratch, 6) scratch followed by injection of PBS, and 7) scratch followed by a second scratch. The extent of the ensuing DCR was assessed 48 h later by measurement of horn weight, by light and electron microscopy, by ranking the DCR, and by the mitotic index. Indomethacin significantly reduced the horn weight in animals treated with scratch but had a much less marked effect on animals treated with PGF2 alpha. Similarly the rank of the DCR and the mitotic index were significantly less in endometria treated by indomethacin with scratch than those treated by indomethacin with PGF2 alpha. From these findings it was concluded that the DCR induced by scratch was inhibited, but not abolished, when preceded by indomethacin. Conversely the DCR induced by PGF2 alpha was not inhibited by indomethacin, thus demonstrating that when local generation of PG is reduced or abolished, PGF2 alpha can sustain the decidual cell response.