Background: Some patients who have short bowel syndrome (SBS) have high intestinal outputs, which increases the risk of dehydration and fluid-electrolyte abnormalities and impairs quality of life. Methods: We evaluated the use of clonidine, an α2-adrenergic receptor agonist, in 2 patients with SBS and high intestinal outputs, who were refractory to conventional therapy with antidiarrheal and antisecretory agents (loperamide, belladonna, opiates, somatostatin, histamine2 receptor antagonists and proton pump inhibitors). The first patient (case 1) was a 29-year-old woman who had 175 cm of small bowel anastamosed to 8 cm of descending colon, ending in a colostomy. The second patient (case 2) was a 22-year-old man who had 30 cm of jejunum anastomosed to 30 cm of sigmoid colon and rectum. Results: The addition of clonidine, 0.1 mg per os (PO) 2 times per day, to the treatment regimen of case 1 decreased her ostomy output from ∼4 L/day to ∼1 L/day, eliminating the need for parenteral nutrition and fluids and decreasing the need for opiate therapy. The addition of clonidine, 0.2 mg PO 2 times per day in case 2 resulted in decreased rectal outputs from ∼4 L/day to ∼1.5 L/day. Conclusions: These results demonstrate that clonidine can effectively reduce intestinal fluid and electrolyte losses and should be considered as an additional treatment option in patients with SBS and high intestinal outputs.