In a previous study we showed that nitric oxide (NO) synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) reduced the number of transient lower esophageal sphincter relaxations (TLESRs) triggered by gastric balloon distention. The role of NO in postprandial TLESRs and gastroesophageal reflux, however, is unknown. Therefore, we studied the effect of L-NMMA on meal-induced TLESRs and reflux episodes with simultaneous recording of esophageal peristalsis, intraesophageal and intragastric pH, and gastric emptying in healthy volunteers. Ingestion of a solid meal resulted in an increase in TLESRs [8.5 (6.3-11.0) 60 min] which was significantly inhibited by L-NMMA [6.0 (4.0-8.8) 60 min, P < 0.05]. In addition, the total number of reflux episodes was reduced. L-NMMA had no effect on intragastric meal distribution and gastric emptying, but attenuated the postprandial increase in intragastric pH. These results confirm the involvement of NO in the neurocircuitry underlying the triggering of TLESRs. The reduction in reflux by L-NMMA has to be confirmed in patients with gastroesophageal reflux disease. NO may be involved in the regulation of gastric acid secretion.