Healthcare-associated pneumonia (HCAP) has been proposed as a new category of pneumonia distinct from community-acquired pneumonia (CAP). A multicenter observational study in 2008 finds that patients with HCAP have a mortality rate significantly higher than patients with CAP, and a worse outcome is associated at logistic regression analysis with a low adherence to empirical antibiotic therapy recommended by ATS/IDSA guidelines. We designed a prospective interventional study to establish whether administration of a broad-spectrum antibiotic therapy consistent with the 2005 ATS/IDSA guidelines has an effect on the clinical outcome of hospitalized patients with HCAP. All patients with HCAP prospectively admitted in 25 medical wards of 20 Italian hospitals during a 1-month period were included in the study. All patients were assigned to receive an empirical therapy including a fluoroquinolone plus an anti-MRSA agent plus either piperacillin-tazobactam or a carbapenem. Main measures for improvement were duration of antibiotic therapy, length of hospital stay, and in-hospital mortality rate. Patients were compared with a historical control group of 90 patients, and followed up to discharge or death. HCAP patients receiving a guideline-concordant therapy had a shorter duration of antibiotic therapy (median 15 vs. 12 days, p = 0.0002), a shorter duration of hospitalization (median 18 vs. 14 days, p = 0.02), and a lower mortality rate (17.8 vs. 7.1 %, p = 0.03). Our results suggest that an empirical broad-spectrum therapy is associated with improved outcome in patients with HCAP.