Sepsis is a serious condition with high morbidity and mortality for which clinical diagnostic criteria lack sensitivity and specificity. Early initiation of appropriate antibiotics and goal directed therapies reduce mortality. Conversely, overuse and misuse of antibiotics, including continuing antibiotics longer than necessary for cure can result in adverse events and add to the increasing problem of antibiotic resistance. Several serum biomarkers have been identified in recent years that have the potential to help diagnose local and systemic infections, differentiate bacterial and fungal infections from viral syndromes or noninfectious conditions, prognosticate, and ultimately guide management, particularly antibiotic therapy. Among these, procalcitonin is the most extensively studied biomarker. Numerous studies have investigated the potential roles of procalcitonin in diagnosing and managing local and systemic infections. However, its clinical utility in the diagnosis and management of patients with suspected infections remains unclear. A Comparative Effectiveness Review (CER) was prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center (BCBSA TEC EPC) on Procalcitonin-Guided Antibiotic Therapy. The objective of the CER was to synthesize comparative studies examining the various uses of procalcitonin in the clinical management of patients with suspected local or systemic infection. The patient populations included those with suspected sepsis or other serious bacterial infections in critically ill adults, neonates with suspected early neonatal sepsis, patients with upper and lower respiratory tract infections, children with fever of unknown source, and postoperative patients with infection. The following Key Question formed the basis for the CER: In selected populations of patients with suspected local or systemic infection, what are the effects of using procalcitonin measurement plus clinical criteria for infection to guide initiation, discontinuation, or a change of antibiotic therapy, when compared with clinical criteria for infection alone on: Intermediate outcomes, such as initiation, discontinuation or change of antibiotic therapy, antibiotic usage, and length of stay? Health outcomes, such as morbidity, mortality, function, quality of life, and adverse events of antibiotic therapy (persistent or recurrent infection, and antibiotic resistance)? Five evidence gaps related to specific populations or comparators were identified in the CER. The evidence gaps are as follows: 1. What are the outcomes of procalcitonin guidance in subgroups of patients who are immunocompromised? 2. What are the outcomes of procalcitonin guidance in pediatric patients? 3. What are the outcomes of procalcitonin guidance in identifying patients at risk of infection who might benefit from pre-emptive antibiotic therapy? 4. Does the use of procalcitonin guidance reduce antibiotic resistance and antibiotic adverse events? 5. How does procalcitonin-guided antibiotic therapy compare to other approaches to reducing unnecessary antibiotic use, such as antibiotic stewardship programs and implementation of practice guidelines?