(1) Background: Hyperkalemia is a common finding in patients with heart failure and reduced ejection fraction (HFrEF), though its prognostic significance is controversial. There is no consensus on optimal potassium levels in these patients. The primary endpoint of this study was to determine the 5-year incidence of hyperkalemia in a cohort of patients with HFrEF. Secondary endpoints were to determine predictors of hyperkalemia and its impact on overall 5-year mortality; (2) Methods: retrospective, longitudinal, single-center observational study of patients with HFrEF followed-up in a specialized unit between 2011 and 2019. Hyperkalemia was considered as potassium concentration > 5.5 mEq/L; (3) Results: Hyperkalemia was observed in 170 (16.8%) of the 1013 patients. The 5-year hyperkalemia-free survival rate was 82.1%. Hyperkalemia was more frequent at the beginning of follow-up. Factors associated with hyperkalemia in the multivariate analysis were baseline potassium (HR 3.13, 95%CI 2.15–4.60;p <0.001), creatinine clearance (HR 0.99, 95%CI 0.98–0.99;p= 0.013), right ventricular function (HR 0.95, 95%CI 0.91–0.99;p= 0.016) and diabetes mellitus (HR 1.40, 95%CI 1.01–1.96;p= 0.047). The overall survival rate at 5 years was 76.4%. Normal–high potassium levels (5–5.5 mEq/L) were inversely associated with mortality (HR 0.60, 95%CI 0.38–0.94;p= 0.025); (4) Conclusions: Hyperkalemia is a common finding in patients with HFrEF with an impact on the optimization of neurohormonal treatment. In our retrospective study, potassium levels in the normal–high range seem to be safe and are not associated with increased mortality.