In 2002, the US Federal government initiated a campaign to vaccinate military personnel and members of the civilian population against smallpox to counter a possible bioterrorism attack. More than 1,200,000 military personnel and approximately 40,000 civilians have been vaccinated since that time. The incidence of myopericarditis in these vaccinees has clearly exceeded calculated background rates and has prompted discussion about cardiac inflammation and other potential vaccine-associated cardiac complications such as dilated cardiomyopathy (DCM) and myocardial ischemia. Although it seems reasonable to predict that some cases of smallpox-associated myopericarditis will progress to DCM, only small numbers have been documented so far, and a causal relationship is difficult to ascertain. With regard to myocardial ischemia, both historical and current data do not suggest a causal association with the vaccine. We describe a case report of myopericarditis following smallpox immunization and provide a review of all cardiac complications associated with vaccination.