In an effort ot elucidate the effectiveness of Cyclosporine A (CyA) relative to the toxicity, Lewis to Sprague-Dawley first and second set skin transplantation and evaluation of the renal function with clearance methods was performed. CyA 12.5 mg/kg/day delayed first set rejection from 12.3 to 15.4 days (p less than 0.001), and second set from 10.5 to 12.1 days (p less than 0.05); 25 mg/kg/day prolonged the survival times to 18.3 (p less than 0.01) and 19.5 (p less than 0.002) days, respectively. The majority of the skin grafts were still not rejected at the end of the 3 weeks CyA 25 mg/kg/day treatment in contrast to the results during 12.5 mg/kg; the second set skin graft survival was significantly better (p less than 0.01) during the higher dosage. It is concluded, that CyA is not fully immunosuppressive at the 12.5 mg/kg/day dosage. In the doses 12.5 and 25 mg/kg GFR (inulin clearance [Cin]) was reduced to 80 and 48%, respectively, of the control value; the lithium clearance (CLi) was reduced to 69 and 27%. Proximal fractional reabsorption, as calculated from 1-CLi/Cin, was increased from a control value of 82% to 86 and 92% (p less than 0.02) in the 12.5 and 25 mg/kg/day group, respectively, suggesting that CyA nephrotoxicity is due to a decrease in the glomerular ultrafiltration pressure rather than being secondary to proximal tubular damage. In conclusion, in this model there does not seem to exist a therapeutic window between nephrotoxicity and the immunological effectiveness of CyA.