A muscarinic receptor subtype 1 (M1) antagonist, pirenzepine, recently has been shown to be relatively free of the usual anticholinergic side effects on esophageal smooth muscle and thus has been implicated for the treatment of gastroesophageal reflux disease (GERD). However, the effect of pirenzepine on GERD remains to be defined. Thirteen patients who demonstrated GERD in a baseline 24-hr ambulatory intraesophageal pH monitoring study were randomized in a double-blind crossover fashion to receive pirenzepine and placebo. An ambulatory 24-hr intraesophageal pH monitor was used to assess reduction in reflux (esophageal pH less than 4.0) with respect to position (upright vs supine), to total number of reflux episodes, and to episodes greater than 5 min. A significant effect for pirenzepine was seen for episodes greater than 5 min (t = 2.61, P = 0.023) and a trend towards significance was seen for total (upright and supine positions combined) percent time of reflux (t = 2.13, P = 0.055). Although not statistically significant, pirenzepine consistently showed greater reduction in all parameters of reflux tested. A greater reduction in percent time of reflux in supine vs upright positions (pirenzepine: 58.9% vs 21.4%; placebo: 43.6% vs 7.3%) may be clinically important in prevention of esophageal injury due to reflux in the recumbent position. Pirenzepine may provide a unique alternative for some GERD patients who may be refractory to other therapies of GERD.