Previous morphological and electrophysiological studies have supported the hypothesis that interstitial cells of Cajal have important regulatory (pacemaker) functions in the gut. In the current study, interstitial cells of Cajal associated with Auerbach's plexus in human small intestine were studied. Freshly resected intestine was examined by light and electron microscopy. The interstitial cells of Cajal resembled modified smooth muscle cells. They had caveolae and dense bodies, an incomplete basal lamina, a very well-developed smooth endoplasmic reticulum, and abundant intermediate (10 nm) filaments. Myosin filaments were not seen. Fibroblast-like cells were distinguished by their lack of caveolae and dense bodies, the relative scarcity of smooth cisternae and intermediate filaments, and the abundant granular endoplasmic reticulum. Interstitial cells of Cajal were arranged in networks of bundles containing processes of two to seven cells with fibroblastlike cells interspersed in the bundles. The bundles were innervated by nerve elements of Auerbach's plexus and extended into both layers of smooth muscle, between muscle cells, and into septa. The bundles were closely associated with elastin fibers. The organization shown in this study strongly supports the concept of interstitial cells of Cajal as important regulatory cells also in the human small intestine. The characteristic cytology and organization of interstitial cells of Cajal may provide a basis for future morphological, electrophysiological, and pathological studies of these cells in human small intestine.