The study was a randomized, single blind, prospective study. Six hundred eighty adults not previously immunized were inoculated with undiluted vaccine, 1:5 dilution, or a 1:10 dilution of vaccinia virus with use of a bifurcated needle. Subjects were monitored for vesicle formation, which is an indicator of the success of vaccination. They were also monitored for adverse events for 56 days after immunization. Results showed that the current stocks of vaccinia virus could be diluted to a titer as low as 10,000 pfu per dose and induce local viral replication and vesicle formation in more than 97 percent of persons. Both the undiluted and diluted vaccines were reactogenic. In addition to the formation of pustules, common adverse events included the formation of satellite lesions, regional aches, fatigue, and chills consistent with the presence of an acute viral illness. Generalized and localized rashes, including two cases of etythema multiforme, were also observed. Only eight subjects did not have a response after two vaccinations. Five of these eight were among the subjects who had preexisting neutralizing antibodies, suggesting that they had been vaccinated as infants. The use of a 1:10 dilution of vaccine in persons that have never been vaccinated, followed by a second vaccination in those with no response after 7 days, could potentially protect nearly ten times as many persons as would be protected by the administration of undiluted vaccine. The rate of adverse reactions to vaccinia vaccine is dependent on age and immune status. Undiluted vaccine resulted in larger areas of inflammation and a higher incidence of regional lymphadenopathy, whereas diluted vaccine resulted in a higher incidence of satellite lesions. Although all subjects in whom vaccination was successful had cellular immune response, the responses were more vigorous in the group that received undiluted vaccine. 2 figures, 4 tables, appendix, 16 references