OBJECTIVES: End Stage Renal Disease (ESRD) is associated with high health care costs and low quality of life (QoL) compared to Chronic Kidney Disease (CKD). The renoprotective effectiveness of ACE inhibitors (ACEi) is largely determined by the ACE insertion deletion (I/D) polymorphism. We determined the cost-effectiveness of ACEi therapy in non-diabetic nephropathy for the ACE II/ID and for the ACE DD genotype. Furthermore, we considered a selective screen-and-treat strategy where patients are prescriped alternative therapy based on their ACE (I/D) polymorphism.  METHODS: Time-dependent Markov models were constructed; cohorts of 1000 patients were followed for 10 years. Data were mainly gathered from the Ramipril Efficacy In Nephropathy (REIN) trial. Both univariate and probabilistic sensitivity analyses were performed. RESULTS: ACEi therapy compared to placebo both reduces costs and improves QALY’s more in the ACE DD group (€105,104 and 0.553 QALYs gained per patient) than in the ACE II/ID group (€15,826 and 0.091 QALYs gained). Sensitivity analyses demonstrated a 30.2% probability of ACEi therapy being not cost-effective in the ACE II/ID group, against an almost 100% probability of cost-effectiveness in the ACE DD group. Cost of dialysis had the largest influence on the cost-effectiveness. An alternative treatment for patients with the ACE II/ID genotype, incorporated in a selective screen-and-treat strategy, should feature a 9.1% increase in survival time for the strategy to be cost-effective. High alternative treatment effectiveness and dialysis costs improve the cost-effectiveness of a screening strategy. CONCLUSIONS: ACEi therapy is a cost saving treatment in non diabetic nephropathy, irrespectively of ACE (I/D) genotype. However, ACEi therapy saved more costs and more health gaines were achieved in the ACE DD genotype than in the ACE II/ID genotype. An alternative treatment featuring a modest increase in survival time for patients with the ACE II/ID genotype can be incorporated in a cost-effective screen-and-treat strategy.