Rectal enemas containing a short-chain fatty acid mixture, butyrate alone, or saline placebo were administered to 47 patients with active distal ulcerative colitis. Enemas were instilled twice daily and the patients' condition was evaluated at entry and after four and eight weeks of local therapy. A disease activity index, chosen as the major end point, decreased significantly after all three modes of treatment with no difference among groups. The endoscopic appearance of the mucosa and the histologic degree of inflammation was not different among groups. After eight weeks, fewer colonic segments were affected endoscopically following butyrate than placebo treatment. This study showed trends towards a beneficial effect of topical short-chain fatty acids in active ulcerative colitis, but more patients are needed to demonstrate this effect with sufficient statistical power.