Because of delays in the manufacturing of the 2000-2001, trivalent inactivated influenza vaccine in the US, there were concerns that there might be shortages of vaccine supply in the US. Therefore, we conducted a prospective, randomized, open-label, multicenter trial at six academic medical centers in the US, to evaluate the immunogenicity of a half dose of inactivated vaccine in healthy adults. Healthy adults between the ages of 18 and 49 were randomized to receive either a full 0.5ml (15.5 microg of each HA antigen) dose or a 0.25ml (7.75 microg of each HA antigen) dose of the 2000-2001 trivalent inactivated influenza vaccine by intramuscular injection. Sera were obtained for assessment of hemagglutination-inhibiting antibody to each of the three strains contained in the vaccine before and 21 days after vaccination. The proportions of individuals achieving a post-vaccination titer of > or =1:40, the geometric mean titers (GMTs) of post-vaccination antibody, and the proportions of individuals with a four-fold or greater increase in antibody were lower for all three strains in those receiving 0.25ml of vaccine compared to those receiving 0.5ml. However, the differences were small for all three antigens. The upper 95% confidence limits for differences between 0.25 and 0.5ml doses were less than 20% for rates of achieving a titer of > or =1:40 and four-fold response, and less than 1.5 for the ratios of GMTs between dose groups, for all three vaccine antigens. These results suggest that when vaccine is in short supply, a strategy using a half dose in healthy adults could increase the number of people vaccinated with relatively little adverse impact on vaccine immunogenicity.