Smallpox vaccination strategies are evolving rapidly and have important implications for human immunodeficiency virus (HIV)-infected persons. Cell-mediated immunity is important for controlling both smallpox and vaccinia. For smallpox, the concern is a substantial increase in the associated mortality rate, which is 30% among healthy persons. For smallpox vaccination, the concern is progressive vaccinia, which is usually lethal but relatively uncommon. The risks associated with both smallpox and vaccinia viruses probably correlate with CD4 cell count, and, as a corollary, the best protection against infection with each is presumably immune reconstitution. It appears that all vaccinations will be voluntary, with 2 recommendations: (1) HIV-infected persons will be advised to decline preemptive vaccination, and (2) in the event of a bioterrorism attack involving smallpox, HIV-infected patients with exposures will be advised to receive vaccine.