The US cases of anthrax in 2001 and the recent severe acute respiratory syndrome outbreak have heightened the need for preparedness and response to naturally emerging and re-emerging infections or deliberately released biological agents. This report describes the response model of the Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (INMI), Rome, Italy for managing patients suspected of or affected by smallpox or viral haemorrhagic fever (VHF) either in the context of an intentional release or natural occurrence. The INMI is Italy's leading hospital in its preparedness and response plan to bioterrorism-related infectious agents. All single and double rooms of INMI are equipped with negative air pressure, sealed doors, high efficiency particulate air (HEPA) filters and a fully-equipped anteroom; moreover, a dedicated high isolation unit with a laboratory next door for the initial diagnostic assays is available for admission of sporadic patients requiring high isolation. For patient transportation, two fully equipped ambulances and two stretcher isolators with a negative pressure section are available. Biomolecular and traditional diagnostic assays are currently performed in the biosafety level 3/4 (BSL 3/4) laboratories. Continuing education and training of hospital staff, consistent application of infection control practices, and availability of adequate personnel protective equipment are additional resources implemented for the care of highly infectious patients and to maintain the readiness of an appropriately trained workforce to handle large scale outbreaks.