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The objective of this study was to determine the incidence of and risk factors for poststernotomy mediastinitis (PSM) due to methicillin-resistant Staphylococcus aureus (MRSA) infection in a hospital in which MRSA was endemic. A retrospective case-control study of patients with PSM after cardiac surgery during January 1997 through July 2002 was conducted. The incidence of PSM was 1.01% (48 of 4746 patients), and 31 episodes (64.6%) were due to MRSA infection. We analyzed the findings for 48 case and 65 control patients. Univariate analysis revealed that the risk factors for PSM were previous hospitalization, resternotomy, chronic renal insufficiency, longer operation time, postoperative heart failure, postoperative renal failure, and reoperation for bleeding. Multivariate analysis revealed that the independent risk factors for PSM were previous hospitalization and reoperation for bleeding. Previous hospitalization was the only significant risk factor for PSM due to MRSA infection. The hospital mortality rate associated with PSM was 41.7%, and there was a higher mortality rate associated with PSM due to MRSA infection.