Background: Daptomycin is considered an effective alternative to vancomycin in patients with methicillin-resistant Staphylococcus aureus bloodstream infection (MRSA BSI). Objective: We investigated the real-world effectiveness of recommended daptomycin doses compared with vancomycin. Methods: This nationwide retrospective cohort study included patients from 124 Veterans’ Affairs hospitals who had a MRSA BSI and were initially treated with vancomycin during 2007–2014. Patients were categorized into 3 groups by daptomycin dose calculated using adjusted body weight: low (>6 mg/kg/day), standard (6–8 mg/kg/day), and high (≥8 mg/kg/day). International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were used to identify other prior or concurrent infections and comorbidities. Multivariate cox regression was used to compare 30-day all-cause mortality as the primary outcome comparing patients on either low-dose, standard-dose, or high-dose daptomycin with vancomycin. Hazard ratio (HR) and 95% confidence intervals (CIs) were reported. Results: Of the 7,518 patients in the cohort, 683 (9.1%) were switched to daptomycin after initial treatment with vancomycin for their MRSA BSI episode. A low dose of daptyomycin was administered to 181 patients (26.5%), a standard dose was given to 377 patients (55.2%), and a high dose was administered to 125 patients (18.3%). Dose groups differed significantly in body mass index (BMI), presence of an osteomyelitis diagnosis, and diagnosis of diabetes. Thirty-day mortality was significantly lower in daptomycin patients than in those given vancomycin (11.3% vs 17.6%; P < .0001). Treatment with daptomycin was associated with improved 30-day survival compared with vancomycin (HR, 0.66; 95% CI, 0.53–0.84), after adjusting for age, BMI, diagnosis of endovascular infection, skin and soft-tissue infection and osteomyelitis, hospitalization in the prior year, immunosuppression, diagnosis of diabetes, and vancomycin minimum inhibitory concentration (MIC). Treatment with a standard dose of daptomycin was associated with lower mortality compared with vancomycin (HR, 0.63; 95% CI, 0.46–0.86). High and low daptomycin dose groups had a trend toward improved 30-day survival compared with vancomycin (Fig. 1). In 2 separate sensitivity analyses excluding vancomycin patients, there was no difference in 30-day mortality between a standard dose and a high dose (HR, 1.01; 95% CI, 0.51–1.97). However, we detected a trend toward poor survival with a low dose compared with a standard dose (HR, 1.21; 95% CI, 0.73–2.02). Conclusions: A standard dose of daptomycin was significantly associated with lower 30-day mortality compared with continued vancomycin treatment. Accurate dosage of daptomycin and avoidance of low-dose daptomycin should be a part of good antibiotic stewardship practice.