Acute and chronic nephrotoxicity directly attributable to cyclosporine (CyA) administration remains an obstacle to its successful use. The studies presented in this report characterize the cytoprotective properties of 16,16-dimethyl prostaglandin E2 in a lethal CyA-induced nephrotoxic rodent model. Wistar-Furth rats (200-250 g) receiving CyA alone (100 mg/kg/day) showed marked deterioration in renal function with severe histologic renal lesions and death of the majority of animals by day 7. The prostaglandin treated group (10/micrograms/kg/day) administered concomitantly with CyA demonstrated near normal renal function and histology by the eighth day after CyA discontinuation, and in a significant improvement in animal survival of 85% (p less than 0.001, n = at least 20 rats/group). These studies demonstrate a novel approach to a major problem with cyclosporine and should have exciting clinical potential.