Protection of the human lung from infectious agents, allergens, and ultrafine particles is difficult with current technologies. High-efficiency particulate air (HEPA) filters remove airborne particles of >0.3 m with 99.97% efficiency, but they are expensive to maintain. Electrostatic precipitation has been used as an inexpensive approach to remove large particles from airflows, but it has a collection efficiency minimum in the submicrometer size range, allowing for a penetration window for some allergens and ultrafine particles. Incorporating soft X-ray irradiation as an in situ component of the electrostatic precipitation process greatly improves capture efficiency of ultrafine particles. Here we demonstrate the removal and inactivation capabilities of soft-X-ray-enhanced electrostatic precipitation technology targeting infectious agents (Bacillus anthracis, Mycobacterium bovis BCG, and poxviruses), allergens, and ultrafine particles. Incorporation of in situ soft X-ray irradiation at low-intensity corona conditions resulted in (i) 2-fold to 9-fold increase in capture efficiency of 200-to 600-nm particles and (ii) a considerable delay in the mean day of death as well as lower overall mortality rates in ectromelia virus (ECTV) cohorts. At the high-intensity corona conditions, nearly complete protection from viral and bacterial respiratory infection was afforded to the murine models for all biological agents tested. When optimized for combined efficient particle removal with limited ozone production, this technology could be incorporated into stand-alone indoor air cleaners or scaled for installation in aircraft cabin, office, and residential heating, ventilating, and air-conditioning (HVAC) systems.T he simple, involuntary act of breathing constantly exposes the human respiratory system to a host of biological and nonbiological particles capable of causing diseases that range from microbial respiratory infections to allergic reactions that may exacerbate underlying asthmatic conditions. Aerosol transmission has been implicated to various degrees in a number of viral and bacterial infections, including smallpox (1), influenza (2), tuberculosis (3), and anthrax (4). Asthma, a chronic respiratory disease that can be triggered by inhalation exposure to diesel soot and allergens, such as fungal spores, pollen, and pet dander, ranked as the fifth most costly health care expenditure in the United States at $51.3 billion in 2006 (5). Considering that citizens of developed nations normally spend 87% of their time indoors (6, 7), properly maintaining indoor air quality is clearly an absolute necessity for the protection of public health.The capture of aerosol particles by filtration is the most common method for air cleaning. High-efficiency particulate air (HEPA) filters, which remove airborne particles of Ͼ0.3 m with 99.97% efficiency, are generally employed for applications requiring the highest level of particle removal. For example, HEPA filters have been incorporated into hospital air handling systems that service o...