OBJECTIVES: Although spironolactone therapy has been shown to significantly improve survival in heart failure (HF), many patients are unable to tolerate spironolactone due to hyperkalemia. Our objective was to estimate the cost-effectiveness of patiromer, a newly approved drug for the treatment of hyperkalemia, plus spironolactone (PS) in patients with NYHA III-IV HF receiving a renin-angiotensin-aldosterone system inhibitor (RAASi, ACE inhibitor or angiotensin receptor blocker) and otherwise unable to tolerate spironolactone due to hyperkalemia. METHODS:  We conducted a cost-utility analysis using a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) for PS with RAASi versus RAASi only in patients with HF and hyperkalemia from the US payer perspective. We enhanced a previous version of the model by considering treatment discontinuation. Clinical parameters were derived primarily from the RALES spironolactone RCT, the OPAL patiromer study, and recent cohort studies of patients with HF. Wholesale acquisition costs were used for drugs and hospitalization costs were derived from HCUP data. Quality of life estimates were based on a prospective study on patients with HF using the EQ-5D. Total direct healthcare costs, quality-adjusted life years (QALYs), and ICER were estimated using a 10-year time horizon and a 3% discount rate. One-way sensitivity analyses were conducted to assess model uncertainty. RESULTS: The average increase in QALYs with addition of patiromer plus spironolactone was 0.27, accompanied by an increase in cost of $15,600, giving an ICER of approximately $57,800/QALY. These findings were driven by the decreased risk of mortality and hospitalization with spironolactone therapy. A limitation is our assumption that the RALES study findings apply to the modeled population, but study findings were robust to sensitivity analyses. CONCLUSIONS: Based on our modeling analysis, use of patiromer to enable spironolactone therapy in NYHA III-IV HF patients may provide a clinical benefit and good economic value.