Renin-angiotensin-aldosterone system inhibitors (RAASi) therapy is commonly used to reduce the risk of death and to slow down disease progression in patients with chronic kidney disease (CKD), heart failure (HF) and hypertension. However, the cardio-renal benefits of RAASi therapy are also associated with an increased risk of hyperkalemia (HK), which may lead to dose reduction or discontinuation of therapy. Patiromer has demonstrated to reduce the risk of HK, which enables to maintain optimal doses of RAASi therapy. This study aimed to assess the cost-effectiveness of patiromer for the management of HK in CKD patients with and without HF in Spain. A Markov model was developed to evaluate the costs and benefits of patiromer for the management of HK in patients with CKD stages 3-4 with and without HF treated with RAASi over a lifetime horizon. The main outcomes included total direct costs (€2021), quality-adjusted life-years (QALYs), life-years gained (LYG) and incremental cost-effectiveness ratio (ICER). Deterministic one-way and probabilistic sensitivity analyses were performed to assess the robustness of the results. Patiromer was more effective compared to no patiromer (5.76 vs 5.57 QALYs; 7.73 vs 7.50 LYG), and resulted in an incremental cost of €3,574, yielding an ICER of €19,092/QALY gained and of €15,236/LYG. Sensitivity analyses suggested that the results were robust to changes in most input parameters. Patiromer is a cost-effective intervention in maintaining normokalemia and enabling optimal RAASi therapy in patients with CKD stages 3-4 with and without HF in Spain.