Human IM-9 B-lymphoblasts have been shown to express the receptor for the neuropeptide substance P (SP). The present study was undertaken to evaluate the effect of sex hormones on this receptor. Testosterone inhibited [125I]SP binding in a dose-dependent manner with an IC50 of approximately 100 nM, while both estradiol and progesterone failed to inhibit SP binding even at concentrations as high as 1 microM. Furthermore, Scatchard analysis indicated that the dissociation constant (Kd) of the SP receptor was markedly increased from 0.25 nM to 2.2 nM when cells were incubated with testosterone. These data indicate a unique neuro-endocrine interaction on lymphocytes involving the substance P receptor.