Atrial septal defect (ASD) is associated with pulmonary hyperperfusion and inflammation and has been linked with increased risk of pneumonia. We investigated the risk of pneumonia in patients with ASD and the impact of ASD closure in a nationwide cohort study. All adults in Denmark (n = 1,168) diagnosed with ASD from 1977 to 2009 were identified through Danish public registries. We compared the risk of hospitalization for pneumonia, use of antibiotics, and mortality with age- and gender-matched general population controls. The median follow-up from time of diagnosis was 9.6 years (range 1 to 33). Cox regression analysis showed that both patients with closed (n = 863) and unclosed (n = 305) ASD had a higher risk of hospitalization for pneumonia (adjusted hazard ratios [HRs] 2.8, 95% confidence interval [CI] 2.3 to 3.5 and 3.1, 95% CI 2.4 to 4.0, respectively) than controls. Patients with ASD also used more antibiotics (adjusted HR for closure 1.4, 95% CI 1.3 to 1.5 and adjusted HR for no closure 1.4, 95% CI 1.2 to 1.6) than the controls. Antibiotic use normalized (adjusted HR 1.1, 95% CI 1.0 to 1.3) and the risk of pneumonia decreased (adjusted HR 1.8, 95% CI 1.1 to 3.0) within 5 years after closure. The proportion of patients with ASD with pneumonia-related death (8.4%) was comparable with that of the general population (9.5%). In conclusion, patients with ASD had a substantially higher risk of hospitalization for pneumonia and used more antibiotics than the general population. The pneumonia risk diminished, but did not completely normalize, 5 years after closure.