Recently, in a monocentre study mycophenolate mofetil (MMF) was demonstrated to be efficacious and safe in penetrating high-risk keratoplasty. Here, preliminary results of a randomized multicentre trial are presented. To date, 86 of 140 scheduled patients undergoing high-risk penetrating keratoplasty have already been randomized into the two study groups: 48 into the MMF group and 38 into the control group. All 86 patients received fluocortolon 1 mg/kg body weight/day, tapered within 3 weeks, and topical prednisolone acetate 1% tapered within 5 months. MMF was administered at a daily oral dose of 2 x 1000 mg for the first 6 postoperative months. Thereafter, MMF was tapered within 2 weeks. The proportion of grafts with immune reactions and side-effects were the main outcome measures. Within an average follow up of 9.2 +/- 6.6 months two patients developed reversible endothelial immune reactions in the MMF group after cessation of MMF application. In the control group, five reversible and three irreversible immune reactions were observed within an average follow up of 10.1 +/- 7.6 months. According to Kaplan and Meier analysis, the ratio of grafts without immune reactions was estimated 89% 1 year postoperatively in the MMF group, in contrast to only 67% in the control group (P = 0.03; log-rank test). Fifteen patients experienced side-effects, especially gastroenterotoxicity, tachycardia, arthralgia or systemic infections. All attributable side-effects were reversible. Systemic MMF may be an effective and safe immune modulating drug in the prophylaxis of immune reactions after penetrating high-risk keratoplasty.