This study was designed to assess the efficacy of i.v. infusion of neostigmine in patients with acute colonic pseudo-obstruction, which was defined as colonic distention with a cecal diameter of at least 10 cm on plain radiographs and no radiographic evidence of mechanical obstruction. Patients who failed to respond to conventional management (nothing by mouth, nasogastric suction, postural changes, i.v. fluids, electrolyte replacement, and discontinuation of any drugs that affect colonic motility) for 24 h were included in the study. Those with bradycardia (heart rate <60/min), hypotension (systolic blood pressure <90 mm Hg), active bronchospasm, clinical or radiographic evidence of perforation, history of partial colonic resection, active gastrointestinal bleeding, pregnancy, or serum creatinine >3 mg/dL were excluded. Twenty patients were included in this prospective, randomized, double-blind, placebo-controlled study. Eleven patients received neostigmine 2.0 mg i.v. over 3-5 min with electrocardiographic monitoring, and 10 received placebo. Patients were evaluated for immediate clinical response (passage of flatus or stools associated with decreased abdominal distention within 30 min) and sustained response with decreased abdominal girth and reduced colonic dilation on radiographs 3 h after infusion. Ten patients in the neostigmine group had an immediate clinical response (median time, 4 min) compared to none in the placebo group (p<0.001). Three patients in the neostigmine group (27%) and eight in the placebo group (80%) failed to show sustained improvement 3 h after infusion (p = 0.04). Eight patients (one-neostigmine; seven-placebo) who failed to respond received open-label treatment with neostigmine. Seven patients responded; one patient from the placebo group failed and eventually required colonic resection. In conclusion, from a total of 18 patients treated with neostigmine, 17 (94%) had immediate clinical response, and 16 (89%) did not have recurrent colonic dilation. The most common side effect was crampy abdominal pain reported in 13 patients, although usually mild (nine). Symptomatic bradycardia requiring atropine occurred in two patients. Two patients in the neostigmine group died, but death was felt not to be related to acute colonic pseudo-obstruction or its treatment.