Ten patients with treatment-resistant left-sided ulcerative colitis were treated in an open protocol with 350 mg cyclosporine enemas nightly for 4 wk. A 12-point clinical disease activity index (DAI) score was calculated at baseline and after 4 wk. Whole blood and colonic tissue cyclosporine concentrations were determined by HPLC at the end of the study. Five of 10 patients responded to treatment, defined as a decrease in the clinical DAI score > or = 3 points. Responders retained the enemas longer than nonresponders (7.5 +/- 1.3 vs. 3.3 +/- 2.2 h, p = 0.01), and there was a positive correlation between decrease in the clinical DAI score and enema retention time (r = 0.64, p = 0.05). The mean colonic tissue cyclosporine concentration was not significantly higher in responders than in nonresponders (2884 +/- 1635 vs. 2359 +/- 576 ng/g, p = 0.52), and the correlation between decrease in the clinical DAI score index and colonic tissue cyclosporine was weak (r = 0.39, p = 0.26). Cyclosporine was undetectable in whole blood samples from all patients, and there were no apparent side effects with treatment. In conclusion, 50% of patients with treatment-resistant left-sided ulcerative colitis significantly improved during therapy with cyclosporine enemas for 4 wk. Patients with longer enema retention times were more likely to respond. A controlled trial is underway to investigate these findings further.