Background: Daptomycin is approved by Health Canada for the treatment of Staphylococcus aureus bacteremia and complicated skin and soft tissue infections caused by gram-positive organisms, but is often used for other indications. We aimed to understand the indications, dosing, and safety profile of daptomycin use in a Canadian inpatient setting. Methods: We included consecutive adult patients who received intravenous daptomycin as inpatients from January 1, 2016, to December 31, 2016, at two tertiary care teaching hospitals in Hamilton, Ontario. Results: We identified 86 courses in 77 unique patients. S. aureus was the most common pathogen ( n = 38, 44%) of which 87% ( n = 33) were methicillin-resistant. The most common indications were bloodstream infections ( n = 31, 36%). The average treatment duration was 10 days, at an average dose of 7.4 mg/kg. The infectious diseases service was consulted in all but two courses. Less than half of treatment courses were given for an indication approved by Health Canada ( n = 41, 48%). Almost half of the unapproved indications ( n = 21, 47%) followed Infectious Diseases Society of America (IDSA) recommendations. Creatine kinase elevation of 3 × the upper limit of normal or higher occurred in a small number of courses ( n = 7, 8%), with only one instance requiring discontinuation of the drug. Conclusions: Daptomycin is being used to treat inpatients for a variety of unapproved indications. Importantly, a sizable portion of these are within IDSA guideline recommendations. Most patients are treated with doses higher than the approved 6 mg/kg without major safety concerns.