Abstract Background and aims: The coronavirus disease 2019 (COVID-19) pandemic affects populations, societies and lives for more than two years. Long-term sequelae of COVID-19, collectively termed the post-acute COVID-19 syndrome, are rapidly emerging across the globe. Here, we investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) antigen persistence underlies the post-acute COVID-19 syndrome. Methods: We performed an endoscopy study with 46 inflammatory bowel disease (IBD) patients 219 days (range: 94-257) after a confirmed COVID-19 infection. SARS-CoV-2 antigen persistence was assessed in the small and large intestine by qPCR of four viral transcripts, immunofluorescence of viral nucleocapsid and virus cultivation from biopsy tissue. Post-acute COVID-19 was assessed by a standardized questionnaire, and a systemic SARS-CoV-2 immune response was evaluated by flow-cytometry and ELISA at endoscopy. IBD activity was evaluated by clinical, biochemical and endoscopic means. Results: We report expression of SARS-CoV-2 RNA in the gut mucosa ~7 months after mild acute COVID-19 in 32 of 46 patients with IBD. Viral nucleocapsid protein persisted in 24 of 46 patients in gut epithelium and CD8+ T cells. Expression of SARS-CoV-2 antigens was not detectable in stool and viral antigen persistence was unrelated to severity of acute COVID-19, immunosuppressive therapy and gut inflammation. We were unable to culture SARS-CoV-2 from gut tissue of patients with viral antigen persistence. Post-acute sequelae of COVID-19 were reported from the majority of patients with viral antigen persistence, but not from patients without viral antigen persistence. Conclusion: Our results indicate that SARS-CoV-2 antigen persistence in infected tissues serves as a basis for post-acute COVID-19. The concept that viral antigen persistence instigates immune perturbation and post-acute COVID-19 requires validation in controlled clinical trials. Preprint PDF From the Discussion: We argue that viral antigen persistence reflects incomplete clearance of SARS-CoV-2 rather than subclinical (latent or persistent) infection, as we were unable to replicate virus from biopsy derived tissue. In line with this, we usually detected only some (but not all) viral transcripts in biopsies from the same patient. Our experimental data rather suggest that immunosuppressive therapy with or without genetic predisposition (affecting the immune system) may promote incomplete viral clearance. In our report, only patients with gut antigen persistence (determined by qPCR) reported post-acute COVID-19 symptoms. In contrast, none of the patients without evidence for antigen persistence in the gut reported symptoms of post-acute COVID-19. This observation strongly argues for a role of viral antigen persistence in post-acute COVID-19 and it appears plausible that SARS-CoV-2 antigen persistence, possibly in infected tissues beyond the gut, could impact host immune responses underlying the post-acute COVID-19 syndrome. Note: They asked patients about post-Covid symptoms, but it isn't clear to me if they asked patients specifically if they had symptoms that appeared or persisted post-Covid or asked them if they had symptoms in general, which they classified as post-Covid symptoms.