Elderly people are at great risk for influenza-related serious complications. However, influenza vaccine-induced antibodies are believed to decline more rapidly in the elderly. This study was designed to evaluate the long-term and cross-reactive immunogenicity among those aged 65 years for two seasonal trivalent influenza vaccines during the 2009-2010 influenza season. One vaccine had the MF59 adjuvant, while the other did not contain an adjuvant. Serum hemagglutinin inhibition (HI) titers were determined pre-vaccination and at 1 and 6 months post-vaccination. Of the 100 subjects, 95 (95%) were followed-up for 1 month after vaccination, and 76 (76%) were followed-up for 6 months after vaccination. Both vaccines met the European Medicines Agency (EMA) criteria 1 month after vaccination. However, seroprotection for influenza B was not satisfactory, with a rate of 55.3% for the MF59 adjuvant vaccine and 47.9% for the vaccine without adjuvant. At 6 months post-vaccination, the MF59-adjuvanted vaccine showed a higher seroprotection rate than the unadjuvanted vaccine. At this point, the MF59-adjuvanated vaccine still met the criteria of EMA for A/H1N1 (62.5% vs. 55.5%, P=0.64) and A/H3N2 (72.5% vs. 47.2%, P=0.04). Both vaccines showed excellent cross-reactive immunogenicity for influenza A/Solomon Island/3/2006 (H1N1) and A/Wisconsin/67/2005 (H3N2), without significant differences. In comparison, cross-reactive immunogenicity was not remarkable for the A/California/7/2009 (H1N1) and A/New Caledonia/20/1999 (H1N1) strains, which have a greater antigenic distance. In conclusion, the MF59-adjuvanted influenza vaccine showed superior long-term immunogenicity in the elderly compared to the unadjuvanted vaccine. However, cross-reactive immunogenicity was not remarkably enhanced with the MF59 adjuvant. J. Med. Virol. 85:1591-1597, 2013. (c) 2013 Wiley Periodicals, Inc.