Five years of normoglycemia following pancreas transplantation (PT) does not ameliorate glomerular lesions in patients with their own kidneys and with long-term insulin-dependent diabetes (IDDM) (Lancet 342:1193, 1993). All these patients received cyclosporine (CsA) as part of their immunosuppression. Here we examined the relationship of CsA dose and blood levels to the presence and severity of CsA-associated renal lesions and changes in renal function in these PT patients. Renal biopsies were taken before (0) and two and five years after PT from 13 non-uremic IDDM patients and were compared with baseline and five year biopsies from 10 IDDM controls (C). CsA dose was reduced from 10 ± 3 mg/kg/day in the first month to 5 ± 2 in the fifth year post-PT. Creatinine clearance (C(Cr)) decreased by 34% at one year post-PT and was stable thereafter, and did not change in C. The decline in C(Cr) from 0 to one year was related to CsA blood levels and dose (P < 0.005) at one year. Cortical interstitial volume fraction [Vv(Int/Cortex)], the index of tubular atrophy, and % sclerotic glomeruli increased significantly from 0 to five years post-PT (P < 0.005, 0.01 and 0.001, respectively), but did not change in C. There was no significant change from 0 to two years post-PT in these lesions, while there was a clear progression from two to five years. Mean CsA dose and blood levels in the first year post-PT correlated with the increase (Δ) in Vv(Int/Cortex) at five years (P < 0.05 for both). The best predictor of Δ Vv(Int/Cortex) was the change in C(Cr) over the first year post-PT (P < 0.003). In conclusion, in five years serious tubulointerstitial and glomerulosclerotic lesions developed in PT recipients on CsA therapy, but not in IDDM C. These lesions were best predicted by the decline in C(Cr) and CsA blood levels and dose during the first year post-PT. Despite early CsA dose reductions, and stabilization of C(Cr), structural lesions progressed from two to five years post-PT.