We present data demonstrating the gene expression of substance P and its receptor in human peripheral blood-isolated monocytes and macrophages. Using the RT-PCR assay, preprotachykinin-A (substance P) mRNA is detected in human peripheral blood-isolated monocytes and macrophages. Among the alpha, beta, and gamma transcripts of the substance P gene, only the beta and gamma transcripts are detectable in these cells. By Southern blot assay these RT-PCR-amplified transcripts are recognized using a specific substance P probe. Sequence analysis of the RT-PCR products from both monocytes and macrophages also confirmed the structure of these transcripts, which are identical to those found in human neuronal cells. At the protein level, both human monocytes and macrophages produced endogenous substance P as determined by an enzyme immunoassay. Capsaicin, a vanillyl fatty acid amide (ingredient of hot pepper), released substance P from both human monocytes and macrophages. In addition, using nested RT-PCR analysis, we identified the presence of mRNA for neurokinin-1 receptor (the receptor for substance P) in human peripheral blood-isolated monocytes and macrophages, which was confirmed by DNA sequencing analysis. The demonstration that human monocytes and macrophages express substance P and its receptor support the notion that substance P is biologically involved in regulating the functions of these cells in an autocrine fashion.