Clinical use of cyclosporin A (CsA) is often limited by nephrotoxicity, which remains a major problem. CsA causes metabolic and distal tubular acidosis. To restore acid–base balance, the kidneys initiate a complex set of responses to induce a net production and release of bicarbonate ions. The aim of this study was to elucidate whether a background of metabolic alkalosis could ameliorates the CsA-induced nephrotoxicity. The experiments were performed on male rats. Seven days after uninephrectomy, rats were divided to 4 groups (n=5 in each group). Metabolic alkalosis was induced by adding 0.28 mol/L NaHCO3 in the drinking water for 7 days, whereas control rats received regular tap water. The bicarbonate pretreated rats were administered either CsA (50 mg/kg, i.p.) or vehicle, daily for a week. At the end of the procedure, animals were placed in metabolic cages for 24 hours and arterial blood was drawn for blood criteria measurements. Creatinine clearance (Ccr), total urine proteins, urine pH and NAG activity were measured. Kidneys were fixed in 10% formaldehyde for histological evaluations. Ccr was significantly affected by the administration of CsA (49.8 ± 1.25 vs. 41.4 ± 1.68 ml/h-1/100g, P<0.05). The effect of CsA on serum pH and [HCO3-] were prevented by pretreatment of NaHCO3. However, it couldn’t prevent CsA-induced increase in NAG activity (1.26 ± 0.32 vs. 1.13 ± 0.210 U/L, P<0.05) and reduction in Ccr. Renal histological data supported the functional findings. Overall, correction of metabolic acidosis couldn’t prevent the CsA-induced reduction in function. These data suggest that there are other factors than acid-base status which may influence CsA-induced nephrotoxicity.