The multidrug resistance protein 1 (MDR1a/b) and the multidrug resistance-related protein 2 (MRP2) are primary active transporters that belong to the ATP-binding cassette (ABC) protein subfamily. They importantly contribute to epithelial secretion of exogenous and endogenous organic compounds. The widely used immunosuppressant cyclosporine A (CsA) is a substrate of MDR1a/b and MRP2, respectively. It interferes with the transport of other MDR1 and MRP2 substrates in the liver. There is evidence for mutual compensation of ABC transporter function within tissues as well as between the liver and the kidney if organic substance transport is disturbed in one of these organs. In the present study, the effects of CsA treatment and kidney-specific MRP2 deficiency on renal and hepatic MDR1a/b and MRP2 expression were examined. Kidney-specific MRP2 deletion was achieved by transplantation of kidneys from MRP2-deficient donors into congenic wild-type recipients. For controls syngenic kidney transplantations were performed between wild-type animals. After three weeks of recovery, animals were randomized to treatment with vehicle or CsA at 10 mg/kg or 30 mg/kg for one week. Transporter expression was studied by real-time PCR and Western-Blot analysis. CsA treatment caused dose-dependent increases in both hepatic and renal cortical MDR1 expression that were similar in animals with and without renal MRP2. On the mRNA level this increase was mainly due to MDR1a induction. Hepatic MRP2 expression was not significantly affected by CsA-treatment or renal MRP2 deficiency. Animals with a functioning renal MRP2 showed dose-dependent increases in renal MRP2 expression.We conclude that CsA treatment causes renal and hepatic MDR1 upregulation which does not depend on the presence of MRP2 in the kidney. In addition, CsA increases MRP2 expression in transplanted kidneys but not in the liver of renal graft recipients.