Fourteen-membered macrolides are known to produce alterations in digestive tract motor activity; these include the induction of strong gastric contractions and a decrease in the motility of the small intestine. The aim of the study was to compare the effects of two different formulations of erythromycin ethylsuccinate (EE) on duodenojejunal motility. Compared with the more commonly used crystalline formulation of EE (CEE), the amorphous formulation (AEE) has previously been described to have greater bioavailability and to induce significantly fewer gastrointestinal side effects when given at therapeutic and what have been considered to be equivalent oral doses (i.e., CEE, 1,000 mg every 12 h; AEE, 500 mg every 12 h). In a crossover double-blind study, duodenojejunal manometric recordings were performed for 10 volunteers treated with placebo, CEE at 1,000 mg, or AEE at 500 mg. Recordings for each volunteer were obtained for a fed period after a standard dinner and then for a nocturnal fasting period. When compared with the placebo, CEE significantly decreased the motility index of the duodenum during the 30 min after the peak serum erythromycin concentrations, shortened the duration of the fed state, and had no effect during the fasting state. In contrast, AEE did not significantly modify any motility parameter. Because AEE produced significantly lower concentrations in serum than CEE, these results do not necessarily imply that the two formulations of EE act differently on the motility of the small intestine.