Respiratory viruses are associated with severe acute exacerbations of chronic obstructive pulmonary disease (COPD) in hospitalized patients. However, exacerbations are increasingly managed in the community, where the role of viruses is unclear. In community exacerbations, the causal association between viruses and exacerbation maybe confounded by random fluctuations in the prevalence of circulating respiratory viruses. Therefore, to determine whether viral respiratory tract infections are causally associated with community exacerbations, a time-matched case-control study was performed. Ninety-two subjects (mean age 72 yrs), with moderate to severe COPD, (mean FEV(1) 40% predicted), were enrolled. Nasopharyngeal swabs for viral multiplex polymerase chain reaction and atypical pneumonia serology were obtained at exacerbation onset. Control samples were collected in synchrony, from a randomly selected stable patient drawn from the same cohort. In 99 weeks of surveillance, there were 148 exacerbations. Odds of viral isolation were 11 times higher in cases, than their time-matched controls (34 discordant case-control pairs; in 31 pairs only the case had virus and in three pairs only control). Picornavirus (26), influenza A (3), parainfluenza 1,2,3 (2), respiratory syncytial virus (1), and adenovirus (1) were detected in cases while adenovirus (1) and picornavirus (2) were detected in controls. In patients with moderate or severe COPD the presence of a virus in upper airway secretions is strongly associated with the development of COPD exacerbations. These data support the causative role of viruses in triggering COPD exacerbations in the community.