The release of neuropeptides, such as substance P (SP) and somatostatin (SOM), from primary sensory nerve fibers has been implicated in the modulation of local immune responses in surface tissues, such as the skin, the pulmonary airways, and the gastrointestinal mucosa. We have investigated the influence of six neuropeptides substance P (SP), somatostatin (SOM), substance K (SK), vasoactive intestinal peptide (VIP), bombesin (BOM), and adrenocorticotropic hormone (ACTH) on the proliferation of resting and partially stimulated human peripheral blood mononuclear leukocytes (PBMLs) and T lymphocytes. Neuropeptides in concentrations from 10-7 to 10-12 M were added to either resting or partially stimulated cells [interleukin-2 (IL-2), concanavalin A (Con A), and phytohemagglutinin (PHA)]. Cellular proliferation was assessed by incorporation of 3H-thymidine after 72 h. With the exception of SP, no significant effect of any of these nenropeptides on aH-thymidine incorporation was found. In resting cells, 10-9 M SP elicits an 80... maximal increase of aH-thymidine incorporation, whereas no statistically significant effect on partially stimulated leukocytes was found. These results contradict a previous report on a significant mitogenic effect of SP on partially stimulated T cells. Considering the very minimal effect of SP on resting cells and, particularly, the absence of an effect on partially stimulated cells, we would question a significant modulatory role for SP and the five other neuropeptides in the proliferation of immunocompetent cells in skin.