Ongoing bioterrorism threats make smallpox vaccination for high-risk persons essential. A second-generation smallpox vaccine, ACAM2000, was approved by the US Food and Drug Administration in 2007. Although generalized vaccinia (GV) and benign cutaneous eruptions are well described following the old smallpox vaccine, risks with ACAM2000 remain unclear. In this case series, Beachkofsky et al review 8 cases of cutaneous reactions following ACAM2000 vaccination, confirming the first case of GV following this vaccine. In addition, 7 cases of a benign, acral, papulovesicular eruption were described. Immunohistochemical antibodies directed against vaccinia proteins may help identify deposits within biopsy specimens of these eruptions.