The situations in which coverage for methicillin-resistant Staphylococcus aureus (MRSA) in the empirical treatment of nosocomial pneumonia (NP) or severe healthcare-associated pneumonia (HCAP) is needed are poorly defined, particularly outside intensive care units (ICUs). Our aim was to characterize if the risk of MRSA NP/HCAP can be defined by clinical variables. We designed an observational, retrospective, multicenter, case-control study to analyze the association between defined clinical variables and risk of MRSA NP/HCAP in non-ICU patients using conditional multivariable logistic regression. Cases and controls (1:2) with microbiological diagnosis were included. Controls were matched for hospital, type of pneumonia (NP or HCAP), and date of isolation. A total of 140 cases (77 NP and 63 HCAP) and 280 controls were studied. The variables associated with the risk of MRSA pneumonia were: (i) respiratory infection/colonization caused by MRSA in the previous year [odds ratio (OR) 14.81, 95% confidence interval (CI) 4.13-53.13, p < 0.001]; (ii) hospitalization in the previous 90 days (OR 2.41, 95% CI 1.21-4.81, p = 0.012); and (iii) age (OR 1.02, 95% CI 1.001-1.05, p = 0.040). The area under the receiver operating characteristic (ROC) curve for the multivariable model was 0.72 (95% CI 0.66-0.78). The multivariate model had a sensitivity of 74.5% (95% CI 65.3-83.6), a specificity of 63.3% (95% CI 56.0-70.6), a positive predictive value of 52.5% (95% CI 43.9-61.2), and a negative predictive value of 82.0% (95% CI 75.3-88.8) for the observed data. Clinical predictors of MRSA NP/HCAP can be used to define a low-risk population in whom coverage against MRSA may not be needed.