Objective:Single-center and regional studies have reported outcomes after treatment with cefiderocol, a novel siderophore cephalosporin. We report on real-world use, clinical outcomes, and microbiological outcomes with cefiderocol therapy within the Veterans’ Health Administration (VHA).Design:Prospective, observational descriptive study.Setting:Veterans’ Health Administration, 132 sites across the United States, during 2019–2022.Patients:This study included patients admitted to any VHA medical center who received cefiderocol for ≥2 days.Methods:Data were obtained from the VHA Corporate Data Warehouse and through manual chart review. We extracted clinical and microbiologic characteristics and outcomes.Results:In total, 8,763,652 patients received 1,142,940,842 prescriptions during the study period. Of these, 48 unique individuals received cefiderocol. The median age of this cohort was 70.5 years (IQR, 60.5–74), and the median Charlson comorbidity score was 6 (IQR, 3–9). The most common infectious syndromes were lower respiratory tract infection in 23 patients (47.9%) and urinary tract infection in 14 patients (29.2%). The most common pathogen cultured wasP. aeruginosain 30 patients (62.5%). The clinical failure rate was 35.4% (17 of 48), and 15 (88.2%) of these 17 patients died within 3 days of clinical failure. The 30-day and 90-day all-cause mortality rates were 27.1% (13 of 48) and 45.8% (22 of 48), respectively. The 30-day and 90-day microbiologic failure rates were 29.2% (14 of 48) and 41.7% (20 of 48), respectively.Conclusions:In this nationwide VHA cohort clinical and microbiologic failure occurred in >30% of patients treated with cefiderocol, and >40% of these died within 90 days. Cefiderocol is not widely used, and many of the patients who received it had substantial comorbidities.