Introduction: The availability of the sodium-free potassium binder patiromer opens new opportunities for hyperkalemia management. Objective: Our objective was to compare data from a 4-year global pharmacovigilance database of adverse events (AEs) reported in patients prescribed patiromer in clinical practice compared with data obtained from the clinical trial program. Methods: Postmarketing safety data regarding patiromer (Veltassa®; Vifor Pharma, Inc.), collected and recorded in the company's global pharmacovigilance database, were analyzed for the period from January 2016 through September 2019. These data were both solicited (i.e., via an organized data-collection method such as a patient-support program) and unsolicited (i.e., voluntarily reported by healthcare professionals, consumers, and competent authorities worldwide). The cumulative annualized mortality rate (events per 100 patient-years [PYs]) for the pharmacovigilance database analysis period were compared with the rate obtained in the longest patiromer clinical trial to date (up to 52 weeks of treatment). For individual AEs, reporting rates (% of events/100 PYs) for events collected in the global pharmacovigilance database were compared with the frequencies (% of patients with event/patients exposed) of events collected in the clinical trial program (N = 666). Results: Over 4 years, the global pharmacovigilance database contained an estimated 45,000 PYs of exposure (17,823 individual case reports and 38,109 AEs), with most cases (95%) from the USA; > 85% of cases utilized 8.4 g/day. In total, 1214 deaths were reported, with a cumulative annualized mortality rate of 2.69/100 PYs (vs. 5.70 deaths/100 PYs in the 52-week clinical trial). Global pharmacovigilance reporting rates for the two most common AEs, constipation and diarrhea, were 6.90 and 3.48%, respectively. Respective frequencies were 7.2 and 4.8% in the clinical trial program. The pharmacovigilance reporting rate for AEs of decreased blood potassium was 0.45%; serum potassium < 3.5 mmol/L was reported in 4.7% of patients in the clinical trial program. For hypomagnesemia or decreased blood magnesium, reporting rates in the postmarketing setting were 0.02 and 0.16%, respectively, and they were observed in 5.3 and 0.8% of patients, respectively, in the clinical trial program. Conclusions: Global pharmacovigilance data over 4 years confirmed that the tolerability and safety of patiromer in clinical practice is predictable and consistent with clinical trial data, with no evidence of any new safety signals to date.