A metabolite of the fungus Streptomyces tsukubaensis was isolated in 1984. It was given the investigative code name FK 506 and was found to have potent immunosuppressive effects in vitro and vivo. In 1989 the first human trials were begun in Pittsburgh. Based on the positive findings of those trials two large multicenter trials were started, one in the United States and one in Europe. In the U.S. trial the study group was treated with FK 506 and corticosteroids at half the dose of the control group. The control group was treated with cyclosporine, azathioprine and corticosteroids. The protocol design grew out of the observations and concerns raised at the early trial in Pittsburgh. The 1-year patient survival was 80% in both groups, and the graft survival was 82% in FK 506 and 79% in the control group (NS). However, at the end of the 1st year 32% of the study group had not had any rejections vs 24% of the control group (p < 0.002). This was accentuated in the pediatric patients, of whom 58% of the FK 506-treated patients were free of rejections vs 28% of the control group at 6 months. The incidence of OKT3 treatment for steroid-resistant rejection was significantly lower (16%) in the FK 506 group compared to the control group (29%); p = 0.0001. The main adverse experiences were renal and neurotoxicity which were more common in the FK 506 patients than in the control group. FK 506 has been used extensively for rescue of treatment-resistant rejections. Unfortunately, no such trials have been randomized.(ABSTRACT TRUNCATED AT 250 WORDS)