In this report we describe the characteristics of human anti-LRH antibodies detected in the serum of a male patient with isolated gonadotropin deficiency. He had received 90 days of therapy with LRH (1 mg, sc, three times daily) and was then placed on three cycles of intermittent therapy (3 weeks of LRH daily, followed by hCG every 3 days for 15 days). At the start of the fourth cycle of therapy with LRH, he developed urticaria at the site of injection, at sites of previous LRH injections, and at distant sites. Upon direct skin testing, the patient reacted positively to 0.02 ng LRH intradermally. A positive intradermal reaction was induced in a normal adult male by preparing his skin with 0.1 ml of the patient's serum and, 24 h later, injecting 0.2 microgram LRH at that site. A binding factor for LRH was detected in the patient's serum by incubation with [125I]LRH. The serum bound 33% of tracer compared to 6% in control serum. We have detected both immunoglobulin G and immunoglobulin E antibodies against LRH in the patient's serum. We have compared displacement of tracer by synthetic LRH with displacement achieved by a series of analogs. Displacements of tracer by LRH, [Lys8]LRH, [D-Trp6,Pro9-NEt]LRH, [des-Gly10]LRH, and [Phe2]LRH were similar, whereas the potencies of Ac-LRH5-10 and AcLRH2-10 were 0.1% or less.