Abstract Background Bacterial infections such as osteomyelitis and endocarditis routinely require several weeks of treatment with intravenous (IV) antimicrobials. Outpatient parenteral antimicrobial therapy (OPAT) programs allow patients to receive IV antimicrobials in an outpatient clinic or at home. The outcomes and costs of such treatments remain uncertain. Methods We conducted a retrospective observational cohort study over a 5-year study interval (1 June 2012 to 31 March 2018) using population-based linked administrative data from British Columbia, Canada. Patients receiving OPAT following a hospitalization for bacterial infection were matched based on infection type and implied duration of IV antimicrobials to patients receiving inpatient parenteral antimicrobial therapy (IPAT). Cumulative adverse events and direct healthcare costs were estimated over a 90-day outcome interval. Results In a matched cohort of 1842 patients, adverse events occurred in 35.6% of OPAT patients and 39.0% of IPAT patients (adjusted odds ratio, 1.04 [95% confidence interval {CI}, .83–1.30; P = .61). Relative to IPAT patients, OPAT patients were significantly more likely to experience hospital readmission (30.5% vs 23.0%) but significantly less likely to experience Clostridioides difficile diarrhea (1.2% vs 3.1%) or death (2.0% vs 8.8%). Estimated mean direct healthcare costs were $30 166 for OPAT patients and $50 038 for IPAT patients (cost ratio, 0.60; average cost savings with OPAT, $17 579 [95% CI, $14 131–$21 027]; P < .001). Conclusions Outpatient IV antimicrobial therapy is associated with a similar overall prevalence of adverse events and with substantial cost savings relative to patients remaining in hospital to complete IV antimicrobials. These findings should inform efforts to expand OPAT use.