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Objective: In March 2018, the US Department of Defense (DOD) added the smallpox vaccination, using ACAM2000, to its routine immunizations, increasing the number of persons receiving the vaccine. The following month, Fort Hood reported a cluster of 5 myopericarditis cases. The Centers for Disease Control and Prevention and the DOD launched an investigation. Methods: The investigation consisted of a review of medical records, establishment of case definitions, causality assessment, patient interviews, and active surveillance. A 2-sided exact rate ratio test was used to compare myopericarditis incidence rates. Results: This investigation identified 4 cases of probable myopericarditis and 1 case of suspected myopericarditis. No alternative etiology was identified as a cause. No additional cases were identified. There was no statistically significant difference in incidence rates between the observed cluster (5.23 per 1000 vaccinated individuals, 95% CI: 1.7–12.2) and the ACAM2000 clinical trial outcomes for symptomatic persons, which was 2.29 per 1000 vaccinated individuals (95% CI: 0.3–8.3). Conclusions: Vaccination with ACAM2000 is the presumptive cause of this cluster. Caution should be exercised before considering vaccination campaigns for smallpox given the clinical morbidity and costs incurred by a case of myopericarditis. Risk of myopericarditis should be carefully weighed with risk of exposure to smallpox. [ABSTRACT FROM AUTHOR]