The aim of this study was to determine the etiology of community-acquired pneumonia (CAP) and the impact of age, comorbidity, and severity on microbial etiologies of such pneumonia. Overall, 395 consecutive patients with CAP were studied prospectively during a 15-mo period. Regular microbial investigation included examination of sputum, blood culture, and serology. Sampling of pleural fluid, transthoracic puncture, tracheobronchial aspiration, and protected specimen brush (PSB) sampling were performed in selected patients. The microbial etiology was determined in 182 of 395 (46%) cases, and 227 pathogens were detected. The five most frequent pathogens were Streptococcus pneumoniae (65 patients [29%]), Haemophilus influenzae (25 patients [11%]), Influenza virus A and B (23 patients [10%]), Legionella sp. (17 patients [8%]), and Chlamydia pneumoniae (15 patients [7%]). Gram-negative enteric bacilli (GNEB) accounted for 13 cases (6%) and Pseudomonas aeruginosa for 12 cases of pneumonia (5%). Patients aged < 60 yr were at risk for an "atypical" bacterial etiology (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.2 to 4.5), especially Mycoplasma pneumoniae (OR: 5.3; 95% CI: 1.7 to 16.8). Comorbid pulmonary, hepatic, and central nervous illnesses, as well as current cigarette smoking and alcohol abuse, were all associated with distinct etiologic patterns. Pneumonia requiring admission to the intensive care unit was independently associated with the pathogens S. pneumoniae (OR: 2.5; 95% CI: 1.3 to 4.7), gram-negative enteric bacilli, and P. aeruginosa (OR: 2.5; 95% CI: 0.99 to 6.5). Clinical and radiographic features of "typical" pneumonia were neither sensitive nor specific for the differentiation of pneumococcal and nonpneumococcal etiologies. These results support a management approach based on the associations between etiology and age, comorbidity, and severity, instead of the traditional syndromic approach to CAP.