We tested the hypothesis that the mucosa of rat jejunum is stimulated by intraluminal D-glucose, resulting in nerve-mediated ion secretion. We examined the D-glucose-induced secretory response in two ways. First, we measured the unidirectional fluxes of sodium and chloride ions, in vivo, during perfusion of segments of jejunum with solution that contained either D-glucose or mannitol. Second, we measured the net rate of absorption of D-glucose from sodium-free solution; this parameter is related to the rate of sodium ion secretion. We used the above two approaches in conjunction with techniques for destroying specific subsets of the intestinal nerves. Thus, we evaluated the subset of intestinal nerves that integrates the secretory response of the mucosa to D-glucose. Jejunal segments perfused with D-glucose solution exhibited significantly greater rates of sodium and chloride ion secretion than did segments perfused with mannitol. Intestinal segments in which the myenteric nerve plexus had been destroyed exhibited a significantly lower rate of sodium ion secretion in the presence of D-glucose than was seen in fully innervated segments. A role for the myenteric nerves in D-glucose-induced ion secretion was also indicated by experiments that involved absorption of D-glucose from sodium-free solution. It was concluded that exposure of the mucosa of rat jejunum to glucose increases the rate of secretion of both sodium and chloride ions. The myenteric nerve plexus is apparently involved in the integration of this mucosal reflex.