OBJECTIVE Recent meta-analyses have suggested similar wound infection rates when using single- or multiple-dose antibiotic prophylaxis in the operative management of closed long bone fractures. In order to assist clinicians in choosing the optimal prophylaxis strategy, we performed a cost-effectiveness analysis comparing single- and multiple-dose prophylaxis. METHODS A cost-effectiveness analysis comparing the two prophylactic strategies was performed using time horizons of 60 days and 1 year. Infection probabilities, costs, and quality-adjusted life days (QALD) for each strategy were estimated from the literature. All costs were reported in 2007 US dollars. A base case analysis was performed for the surgical treatment of a closed ankle fracture. Sensitivity analysis was performed for all variables, including probabilistic sensitivity analysis using Monte Carlo simulation. RESULTS Single-dose prophylaxis results in lower cost and a similar amount of quality-adjusted life days gained. The single-dose strategy had an average cost of $2,576 for an average gain of 272 QALD. Multiple doses had an average cost of $2,596 for 272 QALD gained. These results are sensitive to the incidence of surgical site infection and deep wound infection for the single-dose treatment arm. Probabilistic sensitivity analysis using all model variables also demonstrated preference for the single-dose strategy. CONCLUSIONS Assuming similar infection rates between the prophylactic groups, our results suggest that single-dose prophylaxis is slightly more cost-effective than multiple-dose regimens for the treatment of closed fractures. Extensive sensitivity analysis demonstrates these results to be stable using published meta-analysis infection rates.