The three-dimensional distribution of the peptide-containing innervation in the human intestinal mucosa was studied by fluorescence immunohistochemistry on whole-mount mucosal preparations. An extensive VIP-immunoreactive nerve supply was demonstrated at all levels, but was markedly increased in density in the distal intestine, where it formed a particularly rich network in close contact with the luminal epithelium. In contrast, substance P-containing nerve fibres formed a looser and evenly distributed innervation at all levels. The muscularis mucosae was richly supplied by VIP- and substance P-containing fibres. Met-enkephalin immunoreactivity was confined to a few scattered nerve bundles running in the muscularis mucosae and around the bottom of epithelial crypts.