BACKGROUND: COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation. OBJECTIVE: To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD. METHODS: The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-alpha, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined. RESULTS: Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations. CONCLUSION: This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.