Lesions arising after scab detachment at the smallpox vaccination site have been described in the medical literature. We investigated reports of postscab lesions among US civilian volunteers vaccinated against smallpox from January through August 2003. We conducted enhanced surveillance, using a standard questionnaire, for reports of skin lesions appearing at or near the smallpox vaccination site after scab detachment. We identified 21 reports; 19 of the case patients responded to our questionnaire. The lesions (scab and/or fluid) of 7 case patients were tested for vaccinia virus by use of polymerase chain reaction and/or immunohistochemistry; all were found to be negative. We contacted 18 case patients 11 months after the initial lesion appearance; 10 (56%) of the 18 reported having another lesion appear after the initial postscab lesion had resolved. Lesions were heterogeneous in morphology, clinical appearance, and histology. The evidence from our case series and follow-up suggests that these lesions are self-limited, without significant clinical sequelae.