Study Objectives Continuous intravenous (IV) infusion bumetanide has been associated with severe myalgia in case reports, and the package labeling lists a reported incidence of 0.2% for severe myalgia. The primary objective of this study was to quantify the incidence of bumetanide infusion–induced severe myalgia in patients with acute heart failure (AHF). Secondary objectives were to assess a dose–response relationship between bumetanide infusion rate and occurrence of myalgia and to investigate potential risk factors associated with bumetanide‐induced myalgia. Design Retrospective analysis. Setting Large academic medical center. Patients Adults hospitalized with AHF who required bumetanide (≥ 0.5 mg/hr 464 patients) or furosemide (≥ 20 mg/hr 197 patients) by continuous IV infusion between September 2015 and May 2017. Measurements and Main Results The incidence of severe myalgia with IV furosemide infusion was assessed to measure confounding by indication bias. Electronic medical records were used to identify patients exposed to bumetanide 0.25‐mg/ml or furosemide 2‐mg/ml continuous IV infusions. We defined severe myalgia as a diffuse myalgia with a physician's documented suspicion of bumetanide‐ or furosemide‐induced myalgia unresponsive to electrolyte repletion and necessitating a change to alternative diuretics. The incidence of severe myalgia during bumetanide therapy was 5.8%, with the incidence increasing with higher bumetanide infusion rates: 2.6% for an infusion rate ≤ 1 mg/hour and 10.3% for a rate > 1 mg/hour (p=0.0005). In the multivariate logistic regression analysis, a bumetanide infusion rate > 1 mg/hour was independently associated (odds ratio 4.8, 95% confidence interval 1.94–12.02, p=0.0007) with severe myalgia compared to that with a rate ≤ 1 mg/hour. No patients receiving furosemide continuous IV infusion experienced severe myalgia, although infusion rates were lower in potency than bumetanide infusion rates. Conclusion The incidence of severe myalgia in patients with AHF receiving bumetanide infusion was 5.8%, 29‐fold higher than incidence rate listed in the package labeling. Patients receiving infusion rates > 1 mg/hour were 4‐fold more likely to experience bumetanide‐induced severe myalgia than those receiving rates ≤ 1 mg/hour.