The development of acute insensitivity of pituitary LH secretion to LH-RH after a short exposure to LH-RH is described. In the first experiment, ovariectomized (OVX), phenobarbital-pretreated rats were given pulses of LH-RH (1.25 or 6.25 ng/100 g body weight (b.w.), intravenously). In rats given 1.25 ng at time 0,6.25 ng at 60 min, 1.25 ng at 80 min and 1.25 ng at 120 min, there was a substantial increase in plasma LH after the first two injections, no increase after the third injection and a relatively small increase after the fourth one. In other rats treated identically but not given a 1.25-ng dose at 80 min, the plasma LH rise in response to the 1.25-ng dose at 120 min was comparable to that seen after the 1.25-ng dose given at time 0. If the 1.25-ng LH-RH pulses given at times 0 and 80 min were replaced by a rat pituitary extract, the plasma LH rise in response to the 1.25-ng dose at 120 min was comparable to that seen after administration of pituitary extract. In the second experiment, OVX phenobarbital-pretreated rats were given 1.25 ng LH-RH/100 gb.w. at t = 0. They were then divided into three groups, each receiving 1.25, 3.75 or 6.25 ng LH-RH/100 g b.w. at t = 60 min. Each of these three groups was again divided into three groups which received 1.25 ng LH-RH/100 g b.w. at 80, 100 or 120 min. The response to 1.25 ng LH-RH/100 g b.w. was significantly depressed at t = 80 min in the animals that had received a dose of 3.75 or 6.25 ng LH-RH/100 gb.w. at t = 60 min. At t= 100 min a significantly decreased response was still observed in the animals which had been treated with a dose of 6.25 ng LH-RH/100 g b.w. at t = 60 min. It is concluded that, in the OVX rat, a single dose of LH-RH can induce short-term desensitization of pituitary gland LH release in response to LH-RH. The duration of this short-term desensitization is related to the dose of LH-RH that causes it. This desensitization may have physiological significance in establishing pulsatile rhythms of LH release.