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Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial pneumonia. To characterize pathogen-derived and host-related factors in intensive care unit (ICU) patients with MRSA pneumonia, we evaluated the Improving Medicine through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) database. We performed multivariate regression analyses of 28-day mortality and clinical response using univariate analysis variables at a P level of mec types II (64.1%) and IV (33.1%), and agr I (36.7%) and II (61.8%). Panton-Valentine leukocidin (PVL) was present in 21.9%, and vancomycin heteroresistance was present in 15.9%. Mortality occurred in 37.1% of patients; factors in the univariate analysis were age, APACHE II score, AIDS, cardiac disease, vascular disease, diabetes, SCC mec type II, PVL negativity, and higher vancomycin MIC (all P values were P < 0.001) and age (OR, 1.024; 95% CI, 1.003 to 1.046; P = 0.02). Clinical failure occurred in 36.8% of 201 evaluable patients; the only independent predictor was APACHE II score (OR, 1.082; 95% CI, 1.031 to 1.136; P = 0.002). In summary, APACHE II score (mortality, clinical failure) and age (mortality) were the only independent predictors, which is consistent with severity of illness in ICU patients with MRSA pneumonia. Interestingly, our univariate findings suggest that both pathogen and host factors influence outcomes. As the epidemiology of MRSA pneumonia continues to evolve, both pathogen- and host-related factors should be considered when describing epidemiological trends and outcomes of therapeutic interventions.