This study evaluates the utility and cost effectiveness of empirical and prophylactic antibiotic treatment of leptospirosis compared with conventional management. We developed decision trees comparing empirical antibiotic treatment (within 4-7 days of symptom onset) or prophylaxis to conventional antibiotic treatment (initiated 7 days post-onset). Costs were calculated using both US and Barbados pricing. Empirical treatment provided slightly lower probability of survival, while prophylactic treatment resulted in slightly higher survival rates. Antibiotic treatment initiated after 4-7 symptomatic days was ineffective in preventing serious health outcomes, but cost less with the exception of azithromycin (US pricing). Empirical treatment in Barbados cost less than conventional treatment. Prophylaxis reduced rare serious health outcomes and resulted in significant cost savings for the United States and Barbados. Prophylactic therapy for high-risk individuals or prompt diagnosis and early treatment (before 4 days of symptoms) appear to be cost-effective approaches to prevent severe complications of leptospirosis.