Sympathetic nervous system (SNS) activation mobilizes blood leukocytes. Under these circumstances, both epinephrine (EPI) and neuropeptide Y (NPY) are released. Therefore, we investigated a possible interaction between these transmitters during leukocyte mobilization, using intravenous catheterization of male adult Lewis rats. Intravenous application of NPY followed by EPI, dose-dependently facilitated, intensified and inhibited EPI-induced leukocytosis with subset-specificity for NK-cells, monocytes, and B-lymphocytes. Pharmacological assessment of NPY receptors involved revealed a Y-1R-mediated inhibition and a Y-5R-mediated facilitation. RT-PCR on peripheral blood mononuclear cells (PBMC) detected Y-1R mRNA only, suggesting direct Y-1R-mediated effects on leukocytes and indirect effects via the Y-5R. Thus, via a specific Y-1R/Y-5R interplay, NPY acts as a neuroimmune co-transmitter in vivo.