Since August 2011, a total of 12 human infections with influenza A (H3N2) variant viruses with genes from avian, swine, and human viruses (i.e., A [H3N2]v) that had acquired the M gene from influenza A (H1N1)pdm09 virus have been reported to CDC. Eleven of the cases occurred in children aged <10 years. In six cases, no history of recent exposure to swine was noted, suggesting that human-to-human transmission had occurred. This new gene constellation for A (H3N2)v viruses and its temporal association with an increase in human cases of A (H3N2)v highlight the need to better understand the risk for human infection with these viruses and the extent to which current seasonal vaccines might elicit cross-reactive antibodies to them. CDC conducted a preliminary analysis to evaluate the age-specific presence of serum cross-reactive antibody in U.S. populations vaccinated or not vaccinated with the 2010-11 seasonal trivalent influenza vaccine (TIV). The results indicated that 1) little or no cross-reactive antibody to A (H3N2)v exists among children aged <10 years, 2) immunization with the 2010-11 TIV had no impact on cross-reactive antibody levels in those aged <3 years, 3) cross-reactive antibody was detected in 20%-30% of those aged ≥10 years, and 4) among adults, vaccination with TIV provided a modest boost to the level of cross-reactive A (H3N2)v antibodies. Receipt of seasonal influenza vaccine continues to be recommended to protect against circulating human influenza viruses for all age groups and might provide limited protection against A (H3N2)v infection in the adult population. A vaccine virus specific for A (H3N2)v has been developed and could be used to produce an H3N2v vaccine, if needed.