Risk factors for developing postoperative mediastinitis (POM) due to methicillin-resistant Staphylococcus aureus (MRSA) were analyzed in a case-case control study of patients who underwent median sternotomy during the period from 1994 through 2000. Three patient groups were studied. The first consisted of 64 patients with POM due to MRSA; the second consisted of 79 patients with POM due to methicillin-susceptible S. aureus (MSSA); and the third consisted of 80 uninfected control patients. In multivariable analysis, patients who were diabetic (adjusted OR, 2.86; 95% CI, 1.22-6.70), female (OR, 2.70; 95% CI, 1.25-5.88), and >70 years old (OR, 3.43; 95% CI, 1.53-7.71) were more likely to develop POM due to MRSA. In contrast, the only independent risk factor associated with POM due to MSSA was obesity (OR, 2.49; 95% CI, 1.25-4.96). Antimicrobial prophylaxis consisted primarily of cephalosporin antibiotics (administered to 97% of the patients). Changes in perioperative antimicrobial prophylaxis, in addition to other interventions, should be considered for prevention of POM due to MRSA in targeted, high-risk populations.