In this study, we examined the potential influence of duodenal pH in regulating the occurrence of the interdigestive migrating myoelectric complex (IMMC). Fasting gastroduodenal motility, duodenal pH, and plasma motilin were studied in 15 healthy subjects. During phase I, duodenal pH remained stable at 7 +/- 0.2. Phase II was accompanied by a lowering of duodenal pH, which fluctuated between 2.0 and 7.5. During late phase II, the duodenal pH increased to 6.9 +/- 0.3 and remained in the alkaline range during phase III. In six of 46 episodes of the IMMC, the occurrence of gastric phase III was delayed. This was associated with a persistently low duodenal pH (< 4) during late phase II. Despite a normal cyclic increase of plasma motilin, no gastric phase III activity was observed until the duodenal pH exceeded 7.0. Further studies showed that lowering of duodenal pH by intraduodenal perfusion of HCl prevented the occurrence of gastric phase III. We concluded that regularity of IMMC is governed by duodenal pH. An alkaline pH is essential for the initiation of gastric phase III; lowering of duodenal pH prevents its occurrence despite normal cyclic increase of plasma motilin.