Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial. We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation. We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection. Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% when stable, p = 0.08). Patients with infectious exacerbations (29.7% bacterial, 23.4% viral, 25% viral/bacterial coinfection) had longer hospitalizations (p < 0.02) and greater impairment of several measures of lung function (all p < 0.05) than those with noninfectious exacerbations. Patients with exacerbations with coinfection had more marked lung function impairment (p < 0.02) and longer hospitalizations (p = 0.001). Sputum neutrophils were increased in all exacerbations (p < 0.001) and were related to their severity (p < 0.001), independently of the association with viral or bacterial infections; sputum eosinophils were increased during (p < 0.001) virus-associated exacerbations. Respiratory infections are associated with the majority of COPD exacerbations and their severity, especially those with viral/bacterial coinfection. Airway neutrophilia is related to exacerbation severity regardless of viral and/or bacterial infections. Eosinophilia is a good predictor of viral exacerbations.