Our objective was to assess the clinical factors that would reliably distinguish methicillin-resistant S. aureus (MRSA) from methicillin-susceptible S. aureus (MSSA) endocarditis. A retrospective cohort study of clinical features and mortality in patients with MRSA and MSSA endocarditis between March 1986 and March 2004 was performed in a 750-bed, tertiary care teaching hospital. A total of 32 patients (10 MRSA [31.3%] vs 22 MSSA [68.7%]) were evaluated. Their mean age and sex ratio (male/female) were as follows: 30.8 +/- 16.0 vs 24.4 +/- 19.6 years old and 6/4 vs 13/9, for MRSA and MSSA infective endocarditis (IE), respectively. Univariate and multivariate analyses revealed that persistent bacteremia was significantly more prevalent in MRSA IE (OR, 10.0 [1.480- 67.552]; p, 0.018). There was a higher mortality trend for MRSA IE (50.0%) than for MSSA IE (9.1%) (p=0.019). However, persistent bacteremia was not associated with higher mortality (p > 0.05). These results indicate that if persistent bacteremia is documented, the likelihood of MRSA endocarditis should be viewed as high, and the patient's anti- staphylococcal therapy should be prolonged and/or changed to a more "potent" regimen.