Background: We sought to determine if controlled, prospective clinical data validate the long-standing belief that intravenous (IV) antibiotic therapy is required for the full duration of treatment for 3 invasive bacterial infections: osteomyelitis, bacteremia, and infective endocarditis. Methods: We performed a systematic review of published, prospective, controlled trials that compared IV-only to oral stepdown regimens in the treatment of these diseases. Using the PubMed database, we identified 7 relevant randomized controlled trials (RCTs) of osteomyelitis, 9 of bacteremia, 1 including both osteomyelitis and bacteremia, and 3 of endocarditis, as well as one quasi-experimental endocarditis study. Study results were synthesized via forest plots and funnel charts (for risk of study bias), using RevMan 5.4.1 and Meta-Essentials freeware, respectively. Results: The 21 studies demonstrated either no difference in clinical efficacy, or superiority of oral versus IV-only antimicrobial therapy, including for mortality; in no study was IV-only treatment superior in efficacy. The frequency of catheter-related adverse events and duration of inpatient hospitalization were both greater in IV-only groups. Discussion: Numerous prospective, controlled investigations demonstrate that oral antibiotics are at least as effective, safer, and lead to shorter hospitalizations than IV-only therapy; no contrary data were identified. Treatment guidelines should be modified to indicate that oral therapy is appropriate for reasonably selected patients with osteomyelitis, bacteremia, and endocarditis.