BACKGROUND:Two clinical trials suggest that procalcitonin-guided antibiotic therapy can safely reduce antibiotic prescribing in outpatient management of acute respiratory tract infections (ARTIs) in adults. Yet, it remains unclear whether procalcitonin testing is cost-effective in this setting. OBJECTIVE: To evaluate the cost-effectiveness of procalcitonin-guided antibiotic therapy in outpatient management of ARTIs in adults. DESIGN: Cost-effectiveness model based on results from two published European clinical trials, with all parameters varied widely in sensitivity analyses. PATIENTS: Two hypothetical cohorts were modeled in separate trial-based analyses: adults with ARTIs judged by their physicians to require antibiotics and all adults with ARTIs. INTERVENTIONS: Procalcitonin-guided antibiotic therapy protocols versus usual care. MAIN MEASURES: Costs and cost per antibiotic prescription safely avoided. KEY RESULTS: We estimated the health care system willingness-to-pay threshold as $43 (range $0-$333) per antibiotic safely avoided, reflecting the estimated cost of antibiotic resistance per outpatient antibiotic prescribed. In the cohort including all adult ARTIs judged to require antibiotics by their physicians, procalcitonin cost $31 per antibiotic prescription safely avoided and the likelihood of procalcitonin use being favored compared to usual care was 58.4 % in a probabilistic sensitivity analysis. In the analysis that included all adult ARTIs, procalcitonin cost $149 per antibiotic prescription safely avoided and the likelihood of procalcitonin use being favored was 2.8 %. CONCLUSIONS: Procalcitonin-guided antibiotic therapy for outpatient management of ARTIs in adults would be cost-effective when the costs of antibiotic resistance are considered and procalcitonin testing is limited to adults with ARTIs judged by their physicians to require antibiotics.