The mechanism of induction of the migrating motor complex (MMC) by neural or humoral agents and their role in the control of fasting motility are not well understood. Our aim was to determine the role of extrinsic und intrinsic nerves in mediating the induction of the MMC by motilin. Three groups of dogs were studied. Group I consisted of neurally intact control dogs. In group II, intrinsic neural continuity between the duodenum and the jejunum was interrupted by transection and reanastomosis of the distal duodenum. Dogs in group III underwent disruption of all intrinsic and extrinsic neural input to the entire jejunoileum. Serosal electrodes were sewn to duodenum and jejunum in all dogs. After a 2-week recovery, fasting myoelectric activity was recorded on four or more occasions. Motilin (0.1 µg/kg iv) was given 30 min after a spontaneous duodenal phase III. In group I (controls), motilin induced a premature MMC, which originated in the duodenum and migrated along the small intestine. In group II (intrinsic neural disruption), motilin induced a premature MMC, which began simultaneously in the proximal duodenum and proximal jejunum. In group III (intrinsic and extrinsic neural disruption), motilin induced a premature MMC in the duodenum but not in the jejunum: rather, a short, nonmigrating burst of spike potentials occurred simultaneously in all jejunal electrodes. These observations suggest that extrinsic innervation is necessary for motilin to induce phase III activity in the jejunum. Extrinsic neural pathways appear to mediate motilin-induced MMC activity in the jejunum.