This study aims to identify the impact of new-onset sepsis in patients with chronic obstructive pulmonary disease (COPD) including the effects on acute exacerbations, pneumonia and mortality. Using the National Health Insurance Research Database of Taiwan, all patients with COPD older than 40 years between 1988 and 2010 were recruited. After propensity score matching, each of the 8774 COPD patients with and without sepsis were identified to have similar characteristics. The primary outcome was severe exacerbations of COPD, with a severe exacerbation being defined as a patient requiring hospital admission or an emergency department visit due to COPD. The secondary outcomes were pneumonia, serious pneumonia, and all-cause mortality. The post-index overall cumulative incidence rates of total acute exacerbations were 11.2/person-years in the sepsis group and 6.2/person-years in the non-sepsis group (adjusted hazard ratio (HR) = 1.38, 95% confidence interval (CI), 1.38–1.40). The sepsis group also had higher risks of severe exacerbations (adjusted HR = 2.05, 95% CI, 2.02–2.08), severe exacerbations requiring hospitalization (adjusted HR = 2.30, 95% CI, 2.24–2.36), and severe exacerbations leading to an emergency room visit (adjusted HR = 1.91, 95% CI, 1.87–1.94). Regarding the effect on secondary outcomes, the sepsis group had higher risks of mortality (incidence rate: 23.7/person-years vs. 11.34/person-years, adjusted HR = 2.27, 95% CI, 2.14–2.41), pneumonia (incidence rate: 26.41 per person-days vs. 10.34 per person-days, adjusted HR = 2.70, 95% CI, 2.5–2.91), and serious pneumonia (incidence rate: 5.84 per person-days vs. 1.98 per person-days, adjusted HR = 2.89, 95% CI, 2.5–3.33) compared with the non-sepsis group. Sepsis survivors among patients with COPD had a higher risk of severe exacerbations, pneumonia, serious pneumonia, and mortality compared to patients with COPD without sepsis [Full article]