Mast cells degranulate when exposed to specific antigens (via surface bound IgE), resulting in the release of numerous pro-inflammatory mediators. Neuroregulatory substances also activate mast cells, and may effect differential mediator release, without degranulation, suggesting a role for nerves in modulating mast cell activity. We previously investigated the microanatomical relationships of intestinal mucosal mast cells (IMMC) with nerves and found extensive associations in the intestinal mucosae of rats and humans. The origins of nerves that contact IMMC have not been determined; however, recent morphological and functional studies suggest the possibility that the vagus nerve might be involved. In the current study we show that vagal afferent fibers (labeled by injecting DiI into the nodose ganglion) penetrate to the tips of jejunal villi; and that some of these nerves make intimate contact with IMMC. These data provide the microanatomical basis for direct neural communication between the central nervous system (CNS) and mast cells in the gastrointestinal mucosa.