The development of effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines has been a significant accomplishment. Adverse events are extremely rare, but continued surveillance is important, especially in at-risk populations. In 5 patients with preexisting immune dysregulation, hyperinflammatory syndromes, including hemophagocytic lymphohistiocytosis, developed after SARS-CoV-2 mRNA vaccination. Early recognition of this rare condition is essential. [ABSTRACT FROM AUTHOR]