To determine the causes of treatment failure and to evaluate the prognostic factors in patients hospitalized for community-acquired pneumonia, a prospective, observational study of 228 adult patients hospitalized for a community-acquired pneumonia in the University Hospital of Geneva and the La Chaux-de-Fonds Community Hospital, Switzerland, was conducted. The percentage of patients who failed to improve (as defined by guidelines of the Infectious Disease Society of America) and the causes of treatment failure were assessed, and patients who failed to improve under antimicrobial therapy were compared with those who did improve. In the 54 (24%) patients who failed to improve, a mean increase in length of hospitalization of 4 days was observed. Most causes of treatment failure could be attributed to host factors (61%) rather than to the pathogen (16%) or to an inappropriate antibiotic regimen (3%). After adjusting for potentially confounding variables, concomitant neoplasia (OR 3.25; 95%CI 1.11-9.56), neurological disease (OR 2.34; 95%CI 1.07-5.13), and aspiration pneumonia (OR 2.97; 95%CI 29-6.86]) were associated with failure to improve, whereas monocytosis improved prognosis (OR 0.40; 95%CI 0.20-0.80). Almost one out of four patients hospitalized for community-acquired pneumonia failed to respond to empirical antibiotic treatment. Aspiration pneumonia, concomitant neoplasia, and neurological disease were factors positively associated with failure to improve, whereas monocytosis was linked to a better prognosis.