Several case reports suggested good effects of interferon-alpha in patients with Crohn's disease. In addition, a decreased production of interferon-alpha in Crohn's disease has been shown in vitro. Treatment with interferon-alpha may activate intestinal natural killer cells and down-regulate the overproduction of inflammatory cytokines like interleukin-6 in Crohn's disease. To evaluate the clinical efficacy of interferon-alpha, we treated 12 patients with a chronic active course of Crohn's disease with recombinant human interferon-alpha prospectively for 24 weeks. Prednisolone was continuously tapered and discontinued at week 12. The end point of the study was the prevention of worsening of clinical symptoms defined with the Crohn's disease activity index and was monitored by acute-phase proteins, interleukin-6 serum concentrations, and endoscopy. The biochemical activity of interferon-alpha was measured by 2',5'-oligo adenylate serum levels. The end point of the study was reached in four patients (33%). In these patients the final Crohn's disease activity index was above 150, which means that they did not achieve clinical remission. All other patients (66%) did not respond to interferon-alpha and had to be withdrawn prematurely. Interferon-alpha did not show any beneficial effect on interleukin-6 or acute-phase protein concentrations and on endoscopic activity. The 2',5'-oligo adenylate levels continuously increased during interferon therapy. Considerable side effects were noted. These results fail to demonstrate a therapeutic role of interferon-alpha in chronic active Crohn's disease.