OBJECTIVES The risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia have not been fully characterized and are likely to be different depending on whether infection is acquired in the community or the hospital. METHODS We conducted a case-control study of 619 adults hospitalized between 2005 and 2010 with either MRSA or methicillin-sensitive S. aureus (MSSA) pneumonia. Patients with a respiratory culture within 48 h of hospitalization had community-onset pneumonia whereas patients with a culture collected after this time point had hospital-onset pneumonia. RESULTS Among patients with community-onset disease, the risk for MRSA was increased by tobacco use (OR 2.31, CI 1.23-4.31), chronic obstructive pulmonary disease (OR 3.76, CI 1.74-8.08), and recent antibiotic exposure (OR 4.87, CI 2.35-10.1) in multivariate analysis while patients with hospital-onset disease had an increased MRSA risk with tobacco use (OR 2.66, CI 1.38-5.14), illicit drug use (OR 3.52, CI 2.21-5.59), and recent antibiotic exposure (OR 2.04, CI 3.54-13.01). Hospitalization within the prior three months was associated with decreased risk (OR 0.64, CI 0.46-0.89) in multivariate analysis. CONCLUSIONS This study suggests there are common and distinct risk factors for MRSA pneumonia based on location of onset. The decreased risk for MRSA pneumonia associated with recent hospitalization is unexpected and warrants further investigation. SUMMARY This case-control study showed that there are common and distinct risk factors associated with MRSA pneumonia depending on whether the infection onset is in the hospital or in the community. Recent hospitalization was unexpectedly shown to be associated with decreased risk for MRSA pneumonia and warrants further investigation.