Although effective for bacterial lower respiratory tract infections (LRTIs), antibiotic treatment is often incorrectly prescribed for non-bacterial LRTIs. Procalcitonin has emerged as a promising biomarker to diagnose bacterial infections and guide antibiotic treatment decisions. As part of a regulatory submission to the U.S. Food and Drug Administration, this systematic review and meta-analysis summarizes the effects of procalcitonin-guided antibiotic stewardship on antibiotic use and clinical outcomes in adult LRTI patients. PubMed and the Cochrane Database of Systematic Reviews were searched for English-language randomized controlled trials published between January 2004 and May 2016. Random and fixed effects meta-analyses were performed to study efficacy (initiation of antibiotics, antibiotic use) and safety (mortality, length of hospital stay). Eleven trials were retained, comprising 4090 patients. Procalcitonin-guided patients had lower odds of antibiotic initiation (odds ratio: 0.26; 95% confidence interval [CI]: 0.13–0.52) and shorter mean antibiotic use (weighted mean difference: −2.15 days; 95% CI: −3.30 to −0.99) compared to patients treated with standard care. Procalcitonin use had no adverse impact on mortality (relative risk: 0.94; 95% CI: 0.69–1.28) and length of hospital stay (weighted mean difference: −0.15 days; 95% CI: −0.60 to 0.30). Procalcitonin guidance reduces antibiotic initiation and use among adults with LRTIs with no apparent adverse impact on length of hospital stay or mortality.