The long-term effect of cyclosporine A (CsA) in male Wistar rats with reduced renal mass was studied. The aim of the study was to highlight the relationship of CsA effect on rats, simulating patients with two functioning kidneys (eg, heart, liver transplant recipients) and one kidney (renal transplant recipients). The Wistar rats were subjected to unilateral nephrectomy (Unx, n = 14) and to 5/6 nephrectomy (STnx, n = 14). Half of these rats and half of the sham operated ones (control, n = 13) were administered CsA (10 mg/kg/d) for 28 days IP. The serum creatinine (S(CR)), total protein (S(P)), and urine protein (U(P)) values as well as the whole blood CsA levels were determined on the 28th day of the study. The remnant kidneys were evaluated by image analyses and semiquantitative methods after sacrifice on the 28th day. In the three non-CsA-treated groups (Unx, STnx, and control) S(CR) was significantly higher in STnx rats than in Unx rats (P =.011). Percent of renal scarring (PRS) was significantly higher in Unx (P =.02) and in STnx rats (P =.017), compared with the control group. Among CsA-treated three groups S(CR) was significantly higher in STnx rats compared with Unx (P =.017). In addition, segmental sclerosis rate (SSR) was higher in STnx rats, compared with the control group (P =.008), whereas S(P) was higher in the control group (P =.005). When CsA-treated groups were compared with non-CsA-treated ones, U(P) of the Unx rats not receiving CsA were significantly higher than the Unx rats receiving CsA (P =.026). Also, U(P) was higher in non-CsA-treated groups (P =.014), whereas S(CR) (P =.001), S(P) (P =.001), and PRS (P =.001) were higher in CsA-treated rats. In conclusion, we suggest that preserved renal mass is not enough to prevent CsA toxicity and that CsA should be administered to patients with both kidneys (eg, heart, pancreas recipients) as carefully as to patients with one functioning kidney (renal transplant recipients).