The effects of erythromycin on motor and electrical behavior of the antrum, pylorus, and duodenum were determined in chronically instrumented, awake dogs. Erythromycin infusion resulted in an abrupt, powerful increase in motility. The motility index increased 18-fold in the antrum, 15-fold in the pylorus, and 8-fold in the duodenum. Bradyarrhythmia with a 30% decrease in slow-wave frequency occurred in all animals. Retrograde giant contractions in association with retching and vomiting occurred in 88% of the dogs. Neostigmine was less potent than erythromycin in increasing motility. Hexamethonium given intra-arterially during erythromycin infusion abolished motility for 7.2 +/- 2.9 min and intra-arterial atropine did so for 51 +/- 25 min. Hexamethonium or atropine restored the electrical slow-wave frequency. The results provide evidence that erythromycin action involves cholinergic pathways including ganglionic transmission.