Progressive vaccinia (PV), previously known as vaccinia necrosum, vaccinia gangrenosum, or disseminated vaccinia, is a rare, often fatal adverse event after vaccination with smallpox vaccine, which is made from live vaccinia virus. During recent vaccination programs potential cases of PV were investigated, but none met standard case definitions. PV has not been confirmed to have occurred in the United States since 1987. On March 2, 2009, a U.S. Navy Hospital contacted the Poxvirus Program at CDC to report a possible case of PV in a male military smallpox vaccinee. The service member had been newly diagnosed with acute mylegenous leukemia M0 (AML M0). During evaluation for a chemotherapy-induced neutropenic fever, he was found to have an expanding and nonhealing painless vaccination site 6.5 weeks after receipt of smallpox vaccine. Clinical and laboratory investigation confirmed that the vaccinee met the Brighton Collaboration and CDC adverse event surveillance guideline case definition for PV. This report summarizes the patient's protracted clinical course and the military and civilian interagency governmental, academic, and industry public health contributions to his complex medical management. The quantities of investigational and licensed therapeutics and diagnostics used were greater than anticipated based on existing smallpox preparedness plans. To support future public health needs adequately, the estimated national supply of therapeutics and diagnostic resources required to care for smallpox vaccine adverse events should be reevaluated.