Experience in managing laboratory exposures to potential agents of bioterrorism is limited. The United States Army Medical Research Institute of Infectious Diseases reviewed laboratory exposures involving these agents (1989 to 2002) to assess the effectiveness of medical management. The evaluation of 234 persons (78% vaccinated) for exposure to 289 infectious agents revealed 5 confirmed infections (glanders, Q fever, vaccinia, chikungunya, and Venezuelan equine encephalitis). Postexposure antibiotic prophylaxis was given for most moderate- or high-risk bacterial exposures (41/46; 89%); most unvaccinated minimal-risk (7/10; 70%), and subsets of vaccinated minimal-risk exposures (18/53; 34%) but generally not negligible-risk exposures (6/38; 16%). Vaccine "breakthroughs" were not unexpected (enzootic Venezuelan equine encephalitis, localized vaccinia) or presented with mild symptoms (Q fever). A multifaceted policy of personal protective measures, vaccination, early assessment, and postexposure antibiotic prophylaxis was effective in minimizing morbidity and mortality in at-risk laboratory workers.