The antigenic drift of influenza A (H3N2) virus in 2003-2004 necessitated a change in the vaccine from the A/Panama to the A/Wyoming strain for the 2004-2005 season. Using hemagglutination inhibition, we therefore tested antibodies in sera of 39 individuals (mean age 64.6 years) at the end of the 2003-2004 season for cross-reactivity to vaccine strains and H3N2 antigens subject to antigenic drift. Antibodies against both A (H3N2) Panama and Wyoming developed in 5/13 (38.5%) unvaccinated individuals, whereas, 22/26 (84.6%) vaccinees developed antibodies to Panama and 21/26 (80.8%) to Wyoming. None of these individuals suffered an influenza episode that season. The results suggest that the elderly might develop protective levels of cross-reactive A (H3N2) Wyoming HI antibodies following vaccination with the Panama strain. Such strains, like the ones included in the 2003-2004 influenza vaccine, might be expected to provide a broad-spectrum antibody response that could be effective even in the face of single season antigenic drift.