Rationale: Whether the airway and systemic inflammatory profile in bacterial exacerbations of COPD is distinct from non-bacterial exacerbations is unclear. Previous studies have not employed molecular typing of bacterial pathogens, which is required to accurately define bacterial infection in COPD. The relationship between clinical severity and course of exacerbation and inflammation is also not fully understood. Objectives: To determine if a) systemic and airway inflammation is distinct in new bacterial strain exacerbations, b) clinical severity and resolution of exacerbations is related to airway and systemic inflammation. Methods: In a prospective longitudinal cohort study in COPD, sputum and serum samples obtained prior to, at and following exacerbations during a two year period were studied. Measurements: Clinical information, molecular typing of bacterial pathogens, sputum IL-8, TNF, and neutrophil elastase (NE) and serum CRP. Main Results: From 46 patients, 177 exacerbations were grouped as new strain, pre-existing strain, other pathogen and pathogen negative. New strain exacerbations were associated with significantly greater increases from baseline in sputum TNF and NE and in serum CRP compared to the other three groups. Increases in inflammatory markers were similar among the other three groups. Clinical resolution was accompanied by resolution of inflammation to pre-exacerbation levels, while persistent symptoms were paralleled by persistently elevated inflammation. Clinical exacerbation severity was significantly correlated with levels of all 4 markers. Conclusions: Neutrophilic airway inflammation and systemic inflammation are more intense with well defined bacterial exacerbations than non-bacterial exacerbations. Clinical course of exacerbation and inflammation are closely linked.