Human cytomegalovirus (CMV) infection has been implicated in immunosenescence. To examine the influence of CMV on ability of healthy adults to respond to a novel influenza antigen, the rate of seroconversion and the magnitude of titers to pandemic 2009 H1N1 vaccine was assessed. The clinical trial was stratified by age; 52 persons aged 18–64 and 55 aged 65 and older were enrolled. Among the younger group, 33% had CMV antibody compared with 62% among the older group. No differences by CMV seropositivity in the proportion of participants achieving a seroprotective titer 21 days following the second immunization were noted. However, the geometric mean titer in hemagglutination inhibition assay was significantly higher among CMV seronegative younger participants compared with CMV seropositive younger participants (385 vs. 142, P = 0.013). In contrast, among the older group, CMV serostatus was not associated with differential antibody titers (53 vs. 63, P = 0.75). These data suggest that CMV may shape immune response to neoantigens among younger persons; these groups should be included in future studies of immunosenescence and CMV. J. Med. Virol. 85:1557–1560, 2013. © 2013 Wiley Periodicals, Inc.