Background <p>Kawasaki disease is an idiopathic systemic vasculitis which predominantly occurs in young children. Approximately one third of children with Kawasaki disease have a concurrent acute infection. Several cases of severe and complicated Kawasaki disease in the setting of concurrent adenovirus infection have been described in the literature.</p> Case presentations <p>Four children, between the ages of 9&#xa0;months and 2 ½ years, presented to two centres in South Africa between October 2023 and March 2024 with simultaneous adenovirus infection and Kawasaki disease. All four cases fulfilled American Heart Association 2017 diagnostic criteria for typical Kawasaki disease. Adenovirus infection was confirmed by polymerase chain reaction testing of nasopharyngeal aspirate specimens and, in one case, was further confirmed on pleural fluid analysis. A unifying feature of these four cases was marked severity of Kawasaki disease. All four cases were complicated by macrophage activation syndrome. Two patients exhibited IVIG resistance, defined by recrudescent fever more than 36&#xa0;h after initial IVIG therapy, and two children developed coronary artery abnormalities. These children were primarily managed with IVIG therapy. Two patients received multiple IVIG doses due to IVIG resistance. All four patients received adjuvant steroid therapy, which was indicated for macrophage activation syndrome. All four children were discharged after several weeks. Disease resolution was confirmed at follow up in three of four cases; one patient was lost to follow up.</p> Conclusions <p>These cases are illustrative of the challenges of distinguishing between acute infections and Kawasaki disease, and managing cases with concurrent infection. We postulate that adenovirus infection may trigger immune dysregulation in at-risk children, resulting in a hyperinflammatory syndrome which is clinically consistent with Kawasaki disease and macrophage activation syndrome.</p>