Background: Weaponized Bacillus anthracis is one of the few biological agents that can cause death and disease in sufficient numbers to devastate an urban setting. Objective: To evaluate the cost-effectiveness of strategies for prophylaxis and treatment of an aerosolized B. anthracis bioterror attack. Design: Decision analytic model. Data Sources: We derived probabilities of anthrax exposure, vaccine and treatment characteristics, and their costs and associated clinical outcomes from the medical literature and bioterrorism-preparedness experts. Target Population: Persons living and working in a large metropolitan U.S. city. Time Horizon: Patient lifetime. Perspective: Societal. Intervention: We evaluated 4 postattack strategies: no prophylaxis, vaccination alone, antibiotic prophylaxis alone, or vaccination and antibiotic prophylaxis, as well as preattack vaccination versus no vaccination. Outcome Measures: Costs, quality-adjusted life-years, lifeyears, and incremental cost-effectiveness. Results of Base-Case Analysis: If an aerosolized B. anthracis bioweapon attack occurs, postexposure prophylactic vaccination and antibiotic therapy for those potentially exposed is the most effective (0.33 life-year gained per person) and least costly ($355 saved per person) strategy, as compared with vaccination alone. At low baseline probabilities of attack and exposure, mass previous vaccination of a metropolitan population is more costly ($815 million for a city of 5 million people) and not more effective than no vaccination. Results of Sensitivity Analysis: If prophylactic antibiotics cannot be promptly distributed after exposure, previous vaccination may become cost-effective. Limitations: The probability of exposure and disease critically depends on the probability and mechanism of bioweapon release. Conclusions: In the event of an aerosolized B. anthracis bioweapon attack over an unvaccinated metropolitan U.S. population, postattack prophylactic vaccination and antibiotic therapy is the most effective and least expensive strategy. © 2005 American College of Physicians.