The study will be a four-center, randomized, dose finding trial to evaluate safety, preliminary efficacy, and immunogenicity of Aventis Pasteur smallpox vaccine (APSV) in healthy, vaccinia-naive adults. Four concentrations of APSV, derived from 2 lots of vaccine, will be tested; ranging from 10 (exponent 6 pfu per ml) to 10 (exponent 7.5 pfu per ml). Four concentrations of Dryvax (ranging from 10 exp 6 per ml to 10 exp 8 per ml) will be evaluated as a positive control. This study is designed to assess the feasibility of the use of APSV and dilutions of APSV in an emergency vaccination scenario. The study will be conducted in two phases. The initial phase will consist of a single-center, randomized, open-label study in 45 subjects to evaluate the safety and approximate the take rate of undiluted APSV (two lots APSV plus a Dryvax control arm: n=15 per arm). A 14 day post vaccination safety follow-up will be completed for all subjects vaccinated in the initial phase prior to initiation of the second phase of the study with an additional 285 subjects. All subjects will be followed for 56 days post vaccination with a clinic visit at day 180 for stage 1 subjects and a follow-up phone call at day 180 for stage 2 subjects. The expansion phase of the study will be conducted at three additional sites.