Patients with chronic renal failure frequently have hypogonadism. To elucidate the molecular mechanisms involved, we tested the ability of serum from these patients to inhibit recombinant human luteinizing hormone receptors. Using a cell line expressing functional human luteinizing hormone receptors, we found that adenosine 3'5'-monophosphate (cAMP) production was markedly inhibited by sera from the patients, but not by sera from healthy subjects. Inhibition of cAMP production was associated with inhibition of 125I-human chorionic gonadotropin binding. Inhibition of LH receptors by sera from patients correlated with the glomerular filtration rate and after renal allograft transplantation, decreased. Fractionation of serum samples indicated the receptor-inhibiting activity in proteins of molecular weights from 30,000 to 60,000 Daltons. When characterized and purified, the factor responsible may well be a new LH receptor antagonist of clinical significance.