Both hyperkalemia and hypokalemia may be related to heart failure (HF) therapy and are associated with adverse outcomes. Abnormalities in serum potassium levels in hospitalized patients with HF and reduced ejection fraction (EF) have not been previously investigated. A post hoc analysis was performed in 1,907 hospitalized patients with worsening HF and reduced EF in the placebo arm of the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST) trial. Serum potassium was measured at randomization and at discharge or day 7. The co-primary end points were all-cause mortality (ACM) and cardiovascular mortality or the first HF hospitalization (CVM + HFH). The association between inhospital change in potassium levels and time to outcomes was evaluated using multivariate Cox regression models. Study participants had a mean age of 65.6 ± 12.0 years and were on optimal guideline-directed medical therapies, including β blockers (77%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (85%), and aldosterone antagonists (55%). Baseline potassium concentration was 4.3 ± 0.6 mEq/l, and hyperkalemia or hypokalemia was seen in 6.5% of the participants. On average, serum potassium level increased by 0.21 ± 0.66 mEq/l, p <0.0001, during hospitalization. Inhospital potassium change was not associated with either the primary or the secondary end point over a median follow-up of 9.9 months. In conclusion, in patients with reduced EF hospitalized for worsening HF, serum potassium abnormalities are common at baseline (within 48 hours of admission) and potassium levels increase during hospitalization, despite aggressive diuretic therapy. However, they are not associated with all-cause or CVM or HFH. Inhospital changes in potassium may limit the implementation of evidence-based therapies such as mineralocorticoid receptor antagonists.