To determine the efficacy and safety of short chain fatty acids (SCFA) in the treatment of refractory distal ulcerative colitis (UC). Ten patients with distal UC who had failed to respond to rectal and oral therapy with 5-ASA and corticosteroids were treated with twice daily enemas containing sodium acetate 60 mM, sodium propionate 30 mM, and sodium butyrate 40 mM titrated to a pH of 7. Patients were assessed clinically (rectal bleeding, tenesmus, bowel motions), endoscopically, and histologically before and after 6 wk of therapy. In addition, patients gave a self-assessment of the efficacy of treatment. Five of the 10 patients responded clinically, and four of these had a clinical remission as reflected by a decrease in degree of bleeding (2.2 vs. 1.2, p < 0.05) and tenesmus (1.6 vs. 0.3, p < 0.05) and by global self-assessment. Endoscopic improvement occurred in five (6.78 +/- 0.83 vs. 4.44 +/- 2.7, p < 0.05). Histologically, no improvement was noted. No side effects were noted, and no patient's condition deteriorated. In this open-labeled study in patients with highly refractory distal UC, 50% had an overall clinical and endoscopic response. Forty percent of the patients assessed the treatment to be superior to previous treatments and expressed a desire to continue. This trial confirms other studies as to the efficacy of this treatment and further confirms the need for controlled trials of this promising therapy.