To test the hypothesis that calcium antagonists decrease the incidence and severity of delayed graft function, we conducted three separate, prospective, randomized trials. In these trials, we investigated the effects of diltiazem and those of the prostacycline analogue iloprost. In the first study, 22 control patients and 20 diltiazem patients received grafts perfused with either vehicle or diltiazem 20 mg/L in the Euro-Collins solution. Subsequently, the diltiazem subjects were given the drug as a bolus of 0.28 mg/kg, followed by a continuous infusion of 0.002 mg/min/kg for the following 2 days. Thereafter, diltiazem 60 mg was given to the treated subjects orally for up to 4 years. In the second study, 11 control subjects and 10 diltiazem subjects received the same postoperative regimen, but all grafts were harvested without addition of diltiazem to the perfusion solution. In the third protocol, four groups were studied as follows: 19 control subjects who received no specific treatment, 16 subjects who received diltiazem, 16 subjects who were given iloprost, and 14 subjects who received both iliprost and diltiazem. The donor kidney of treated patients was perfused with either diltiazem, iloprost, or both drugs. Primary graft function occurred more commonly in the groups receiving diltiazem. Further, in the first study the number of hemodialyses per patient was reduced in those patients with delayed graft function. Fewer rejection episodes occurred in patients receiving diltiazem. Plasma levels of soluble interleukin-2 receptors decreased significantly during diltiazem treatment. Moreover, renal biopsies showed less severe signs of cyclosporin-A (CyA) nephrotaxicity in diltiazem-treated patients compared to controls, even though these patients also exhibited higher CyA trough levels. In the third study, the decrease in serum creatinine levels was more rapid in patients receiving diltiazem, with or without iloprost. After I-year follow-up in this study, patients with primary graft function had lower creatinine values than those with delayed graft function. The long-term follow-up of diltiazem-treated patients in the first 2 studies showed significantly lower serum creatinine levels at 2 years and a tendency of an improved graft survival up to 4 years (80% vs. 70%) compared to patients not given diltiazem. We conclude that diltiazem may blunt ischemic graji failure, and may be of value in preventing acute and chronic CyA nephrotoxicity.