Smallpox vaccination is associated with several potential cutaneous adverse reactions, ranging from benign self-limited hypersensitivity reactions to life-threatening eczema vaccinatum and progressive vaccinia. Acral papulovesicular eruption is a distinct presentation that has been described in US Military service members following vaccination with the second-generation smallpox vaccine (ACAM2000, Sanofi Pasteur Biologics Co). We describe a case of this unique cutaneous eruption and review previously described cutaneous adverse events associated with smallpox vaccination.