Older adults are more vulnerable to influenza virus infection and at higher risk for severe complications and influenza-related death compared to younger adults. Unfortunately, influenza vaccine responses tend to be impaired in older adults due to aging of the immune system (immunosenescence). Latent infection with cytomegalovirus (CMV) is assumed to enhance age-associated deleterious changes of the immune system. Although lower responses to influenza vaccination were reported in CMV-seropositive compared to CMV-seronegative adults and elderly, beneficial effects of CMV infection were observed as well. The lack of consensus in literature on the effect of latent CMV infection on influenza vaccination may be due to the presence of pre-existing immunity to influenza in these studies influencing the subsequent influenza vaccine response. We had the unique opportunity to evaluate the effect of age and latent CMV infection on the antibody response to the novel influenza H1N1pdm vaccine strain during the pandemic of 2009, thereby reducing the effect of pre-existing immunity on the vaccine-induced antibody response. This analysis was performed in a large study population (n = 263) in adults (18–52 years old). As a control, memory responses to the seasonal vaccination, including the same H1N1pdm and an H3N2 strain, were investigated in the subsequent season 2010–2011. With higher age, we found decreased antibody responses to the pandemic vaccination even within this age range, indicating signs of immunosenescence to this novel antigen in the study population. Using a generalized estimation equation regression model, adjusted for age, sex, and previous influenza vaccinations, we observed that CMV infection in contrast did not influence the influenza virus-specific antibody titer after H1N1pdm vaccination. Yet, we found higher residual protection rates (antibody level ≥40 hemagglutinin units (HAU)) in CMV-seropositive individuals than in CMV-seronegative individuals 6 months and 1 year after pandemic vaccination. In the subsequent season, no effect of age or CMV infection on seasonal influenza vaccine response was observed. In conclusion, we observed no evidence for CMV-induced impairment of antibody responses to a novel influenza strain vaccine in adults. If anything, our data suggest that there might be a beneficial effect of latent CMV infection on the protection rate after novel influenza vaccination.