Background: Severe gastrointestinal (GI) involvement has been occasionally reported in children with SARS-CoV-2 infection or among those with multisystem inflammatory syndrome (MIS-C). We aimed to investigate the clinical, radiological and histopathological GI characteristics in order to identify factors associated with severe outcome.Methods: In this multicenter retrospective nationwide cohort study, symptomatic children with laboratory confirmed SARS-CoV-2 infection or MIS-C were enrolled. Children who received a diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, diffuse adeno-mesenteritis or abdominal fluid collections requiring surgical consultation and temporally correlated with SARS-CoV-2 infection were classified as having a severe GI involvement. Logistic regression models were used to estimate odds ratios (OR [95% confidence intervals]) between potential explanatory factors and severe outcome.Findings: 685 children were enrolled between February 2020 and January 2021. The presence of GI symptoms was associated with a higher chance of hospital admission (OR 2·64 [1·89–3·69]) and of intensive care support (OR 3·90 [1·98–7·68]).Overall, 65 children (9.5%) showed a severe GI involvement featuring atypical presentations including disseminated adeno-mesenteritis (39·6%), appendicitis (33·5%), abdominal fluid collections (21·3%), pancreatitis (6·9%) or ileal intussusception (4·6%). Twenty-seven (42%) of these children underwent surgery, and remarkably only half of clinically suspected appendicitis were histologically confirmed. Children aged 5-10 years (OR 8·33 [2·62–26·5]) or > 10 years of age (OR 6·37 [2·12-19·1]) had a higher chance of severe outcome, compared to preschool-age children. Severe GI outcomes were more frequent in patients with abdominal pain (aOR 34·5 [10·1–118]), lymphopenia (aOR 8·93 [3·03-26·3]) or MIS-C (aOR 6·28 [1·92–20·5]). Diarrhea was associated with a higher chance of adeno-mesenteritis (aOR 3·13 [1·08–9·12]) and abdominal fluid collections (aOR 3·22 [1·03-10]).Interpretation: About 10% of symptomatic children with COVID-19 may have severe GI involvement, frequently associated with MIS-C. Early identification of at-risk patients can improve the management of serious complications.Funding Statement: None.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study protocol was approved by the Ethical Committee of the coordinating center (protocol number 0031296) as well as by independent ethics committees and/or institutional review boards of any single enrolling center.