Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's ‘Animal Rule’. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.