Over the past several years, funding for biodefense research has increased dramatically, leading to the possibility of increased laboratory-acquired infections with potential bioterrorism agents. The Special Immunizations Program at United States Army Medical Research Institute of Infectious Diseases reviewed its policy and management of potential occupational exposures (1989-2002) to assess guidelines for determining the risk of exposure and disease and to determine criteria for initiating postexposure prophylaxis (PEP). Initiating antibiotic PEP was based primarily on exposure risk but was also influenced by vaccination status and agent virulence. PEP was given to nearly all moderate- and high-risk bacterial exposures, regardless of vaccination status, to most unvaccinated and subsets of vaccinated minimal-risk exposures, but generally not to negligible-risk exposures. Algorithms for evaluating and managing potential exposures are presented to provide guidance to other agencies as they begin to work with these agents.