The objective of the study was to compare the outcome of poststernotomy mediastinitis (PSM) caused by methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA, respectively). Hospital records of 41 patients with S. aureus PSM who were all treated by closed drainage from 1 April 1996 through 1 February 2000 were reviewed. PSM was caused by MRSA in 15 patients and by MSSA in 26. Follow-up (+/-SD) averaged 12.5+/-14.0 months per patient. Both groups had similar perioperative characteristics. Patients with MRSA PSM had a significantly lower actuarial survival rate than did patients with MSSA PSM (60.0%+/-12.6%, 52.5%+/-3.4%, and 26.3%+/-19.7% versus 84.6%+/-7.1%, 79.0%+/-8.6%, and 79.0%+/-8.65 at 1 month, and at 1 and 3 years, respectively; values are +/- SD; P=.04). PSM-related death and treatment failure were significantly higher in the MRSA group than in the MSSA group (P=.03 and.02, respectively). Logistic regression analysis revealed that MRSA was the only independent risk factor for overall mortality. In conclusion, the clinical outcome of PSM caused by MRSA is poorer than that caused by MSSA.