Numerous studies have explored whether the antibody response to influenza vaccination in elderly adults is as strong as it is in young adults. Results vary, but tend to indicate lower post-vaccination titers (antibody levels) in the elderly, supporting the concept of immunosenescence-the weakening of the immunological response related to age. Because the elderly in such studies typically have been vaccinated against influenza before enrollment, a confounding of effects occurs between age, and previous exposures, as a potential extrinsic reason for immunosenescence. We conducted a four-year study of serial annual immunizations with inactivated trivalent influenza vaccines in 136 young adults (16 to 39 years) and 122 elderly adults (62 to 92 years). Compared to data sets of previously published studies, which were designed to investigate the effect of age, this detailed longitudinal study with multiple vaccinations allowed us to also study the effect of prior vaccination history on the response to a vaccine. In response to the first vaccination, young adults produced higher post-vaccination titers, accounting for pre-vaccination titers, than elderly adults. However, upon subsequent vaccinations the difference in response to vaccination between the young and elderly age groups declined rapidly. Although age is an important factor when modeling the outcome of the first vaccination, this term lost its relevance with successive vaccinations. In fact, when we examined the data with the assumption that the elderly group had received (on average) as few as two vaccinations prior to our study, the difference due to age disappeared. Our analyses therefore show that the initial difference between the two age groups in their response to vaccination may not be uniquely explained by immunosenescence due to ageing of the immune system, but could equally be the result of the different pre-study vaccination and infection histories in the elderly.