Ten ischemic cardiac events (ICEs) were reported among 37,901 initial US Department of Health and Human Services (DHHS) smallpox vaccinees. Symptoms developed a median of 10 days after vaccination (range, 0-28 days). The median age of case patients was 56 years (range, 42-65 years), and 60% were male. Seven (70%) of the case patients had ≥3 cardiac risk factors or probable coronary artery disease before vaccination. Two women, 55 and 57 years of age, experienced acute myocardial infarction and fatal cardiac arrests. Background rates of ICEs during a 3-week period for civilian populations that were age and sex matched to DHHS vaccinees were estimated. The observed number of myocardial infarctions exceeded estimated expectations (5 vs. 2) but remained within the 95% predictive interval (PI) (0.6-5.4). New onset angina was observed significantly less frequently than estimated expectations (1 vs. 10; 95% PI, 3.5-15.7). After persons with ≥3 cardiac risk factors or known heart disease were deferred from vaccination, no ICEs were reported among an additional 6638 vaccinees. © 2008 by the Infectious Diseases Society of America. All rights reserved.