Inappropriate initial antimicrobial therapy (IIAT) has been associated with decreased survival in patients with health care-associated pneumonia (HCAP). We performed a study to determine whether empiric HCAP antibiotic regimens targeting methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are associated with greater appropriate therapy. A retrospective cohort study of culture-positive HCAP over 6 years (January 2003-December 2008) was performed at Barnes-Jewish Hospital, a 1200-bed urban teaching hospital. We identified 757 consecutive patients with HCAP. IIAT was administered to 213 (28%) patients. The pathogens most frequently associated with IIAT included P. aeruginosa (n = 60, 28%), MRSA (n = 58, 27%), and Acinetobacter species (n = 32, 15%).Multivariate logistic regression analysis demonstrated that empiric anti-pseudomonal antibiotics (adjusted odds ratio [AOR], 1.75; 95% confidence interval [CI], 1.34-2.29; p = 0.036), empiric anti-MRSA antibiotics (AOR, 1.71; 95% CI, 1.36-2.14; p = 0.018), infection with Streptococcus pneumoniae (AOR, 2.82; 95% CI, 2.03-3.91; p = 0.002), absence of Acinetobacter species infection (AOR, 10.57; 95% CI, 7.29-15.33; p < 0.001), absence of P. aeruginosa infection (AOR, 1.69; 95% CI, 1.36-2.05; p = 0.014), and absence of Stenotrophomonas maltophilia infection (AOR, 20.43; 95% CI, 9.35-44.66; p < 0.001) are independent predictors of appropriate therapy for HCAP. Our study suggests that initial therapy for HCAP should include antibiotics targeting MRSA and P. aeruginosa in order to provide appropriate initial therapy. However, the selection of individual antibiotic agents should be based on local patterns of infection and adjusted when microbiology results become available.