We performed a cost-effectiveness analysis to evaluate whether patients with artificial joints should take penicillin, erythromycin, or no antibiotics before dental procedures. We modeled the risk of anaphylaxis from penicillin, the risks and consequences of an artificial joint infection, and the actual variable costs of hospitalization and antibiotics. Penicillin prophylaxis is slightly less expensive than erythromycin prophylaxis but is both more expensive and less effective than no prophylaxis. Erythromycin prophylaxis, the most effective, is the most expensive strategy. The marginal cost effectiveness of erythromycin prophylaxis compared to no prophylaxis is $12,900 per quality-adjusted year of life saved. Sensitivity analysis demonstrates that the risk of developing a joint infection is the key parameter in the analysis. Based on our estimated risk of developing a joint infection, the cost-effectiveness of antibiotic prophylaxis with erythromycin compares favorably with other medical interventions. Thus, until a definitive study to quantify the risk is conducted, patients with artificial joints should take prophylactic erythromycin when they undergo dental procedures.