In December 2002, the Department of Defense re-instituted smallpox vaccination for US military forces following growing concerns that smallpox might be employed as a bioterrorist weapon. More than one million service members have been given the smallpox vaccine since 2002, although there have been concerns about the safety of the vaccine. Using a large self-reported prospective database, this analysis investigated a wide variety of self-reported health outcomes and possible association with smallpox vaccination. After confirming self-reported vaccination history with electronic vaccine data, 40,472 individuals were included in the analyses, 8,793 of whom received the smallpox vaccine and 31,679 who did not. No significant adverse associations between smallpox vaccination and self-reported health outcomes, including mental and physical functioning, cardiovascular diseases, and autoimmune disorders, were found. These findings complement studies that utilize other data sources, such as electronic hospitalization records, and may be reassuring to health care providers and those who receive the smallpox vaccination.