Community-acquired pneumonia (CAP) is a frequent event in patients with COPD, although it is not currently considered an acute exacerbation of COPD (AECOPD). To our knowledge, no studies have compared the inflammatory response of patients with COPD who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biologic signaling of AECOPD and CAP + COPD. Prospective data were collected from 249 consecutively hospitalized patients with COPD. Comparative analyses were performed in patients with AECOPD (n = 133) and patients with CAP + COPD (n = 116). Measures of clinical characteristics, blood biomarkers, and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30 days, 90 days, and 1 year. Patients with CAP + COPD had higher FEV1 compared with patients with COPD without pneumonia. In-hospital and long-term outcomes (1 year) were similar for both populations. However, patients with AECOPD had more readmissions, and patients with CAP had more prior episodes of pneumonia. At day 1 and day 3, patients with CAP + COPD had significantly (P < .001) higher serum levels of C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α, and IL-6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy, and noninfectious AECOPD cause confirmed higher levels of the same biomarkers in patients with CAP + COPD. Chills, pleuritic pain, sputum purulence, and CRP levels at day 1 were independent clinical predictors of CAP + COPD. Our study confirms that two different clinical and inflammatory profiles exist in hospitalized patients with COPD in response to CAP (stronger response) and AECOPD, although with similar short-term and long-term outcomes.