ABSTRACT: BACKGROUND:Infection is a leading cause of hospitalization with high morbidity and mortality, but there are limited data to guide the duration of antibiotic therapy. PURPOSE:Systematic review to compare outcomes of shorter versus longer antibiotic courses among hospitalized adults and adolescents. DATA SOURCES:MEDLINE and Embase databases, 1990-2017. STUDY SELECTION:Inclusion criteria were human randomized controlled trials (RCTs) in English comparing a prespecified short course of antibiotics to a longer course for treatment of infection in hospitalized adults and adolescents aged 12 years and older. DATA EXTRACTION:Two authors independently extracted study characteristics, methods of statistical analysis, outcomes, and risk of bias. DATA SYNTHESIS:Of 5187 unique citations identified, 19 RCTs comprising 2867 patients met our inclusion criteria, including the following: 9 noninferiority trials, 1 superiority design trial, and 9 pilot studies. Across 13 studies evaluating 1727 patients, no significant difference in clinical efficacy was observed (d = 1.6% [95% confidence interval (CI), -1.0%-4.2%]). No significant difference was detected in microbiologic cure (8 studies, d = 1.2% [95% CI, -4.1%-6.4%]), short-term mortality (8 studies, d = 0.3% [95% CI, -1.2%-1.8%]), longer-term mortality (3 studies, d = -0.4% [95% CI, -6.3%-5.5%]), or recurrence (10 studies, d = 2.1% [95% CI, -1.2%-5.3%]). Heterogeneity across studies was not significant for any of the primary outcomes. CONCLUSIONS:Based on the available literature, shorter courses of antibiotics can be safely utilized in hospitalized patients with common infections, including pneumonia, urinary tract infection, and intra-abdominal infection, to achieve clinical and microbiologic resolution without adverse effects on mortality or recurrence.