Rapamycin (RAPA) acts synergistically with cyclosporine (CsA) to achieve powerful immunosuppression in several animal models of organ transplantation and autoimmune disease. If these drugs are to be used together, they should not enhance toxicity. Thus, we examined the effects of combining CsA and RAPA on renal structure and function in a rat model of chronic CSA nephropathy. Rats were given placebo, CSA (2, 4, and 8 mg/kg), RAPA (0.01 and 0.1 mg/kg), or CsA+RAPA for 28 days while on a low-salt diet. RAPA at a subtherapeutic dose of 0.1 mg/kg worsened glucose metabolism and potentiated chronic nephrotoxicity induced by CsA at 8 mg/kg in terms of both renal function and structural injury. Since hyperglycemia is known to accelerate fibrotic processes, the impairment of glucose metabolism may play a role in tubulointerstitial fibrosis (plasma glucose vs. tubulointerstitial fibrosis, r=0.72, n=18, P<0.001). RAPA had to be given at a dose 10-fold lower (0.01 mg/kg) and CsA at a dose 4-fold lower (2 mg/kg) than the dose required for complete immunosuppression to minimize nephrotoxicity. Although the CsA+RAPA combination acts synergistically on immunosuppression, the combination at the subtherapeutic dose of each drug may be synergistically nephrotoxic, perhaps due to hyperglycemia. Clinical combinations of CsA and RAPA must be tested carefully for chronic nephrotoxicity.