Patients with atrial septal defect (ASD) have higher mortality and higher risk of atrial fibrillation, heart failure, pneumonia, and stroke than the general population even if the ASD closes spontaneously in childhood. The reason for the long-term complications remains unknown. Since many of the complications can be linked up with alterations in inflammatory response, we speculate that inflammation may contribute to the association between ASD and morbidity and mortality. We investigated inflammatory activity in adults with an ASD compared with controls. We included 126 adults with an unrepaired ASD. A group of healthy controls were recruited as comparison group (n = 23). Serum samples were analyzed for 92 inflammation-related protein biomarkers using a proximity extension assay. A pathway enrichment analysis was performed using Reactome database. Out of 92 biomarkers, 73 were eligible for data analysis. Increased levels of 14 (19%) biomarkers were found in patients with open ASD and 24 (33%) biomarkers in patients with spontaneously closed defects compared with controls (p < 0.05). Multiple inflammatory pathways showed stronger enrichment in both patient groups when compared with controls. In conclusion, inflammatory activity is altered in adult patients with an unrepaired ASD compared with healthy controls. The increased inflammatory burden of patients with an unrepaired ASD may contribute to the development of morbidities.