As the regional influenza reference centre operating within the Italian network InfluNet, here we report data on virological and epidemiological surveillance of influenza, as well as on the vaccination coverage rates achieved in Lombardy (Northern Italy) over 10 consecutive winter seasons (2004-2014).   Over the past 10 years, influenza vaccine coverage declined both in the general population (from 15.7% in 2004-2005 to 11.7% in 2013-2014) and in the vaccine-target population of individuals ≥65-y-of-age (from 65.3% in 2004-2005 to 48.6% in 2013-2014) and is far below the minimum planned threshold level (75%). The highest influenza-like illness (ILI) rates were recorded during the 2004-2005 and 2009-2010 epidemics (peak incidence: 12.04‰ and 13.28‰, respectively). Both seasons were characterised by the introduction of novel viral strains: A/Fujian/411/2002(H3N2) (a drifted hemagglutinin variant) and A/California/7/2009(H1N1) pandemic virus (a swine origin quadruple reassortant), respectively. Because the antigenic match between vaccine and circulating strains was good in both of these seasons, a relevant proportion of cases may have been prevented by vaccination. A different situation was observed during the 2011-2012 season, when ILI morbidity rates in individuals ≥65-y-of-age were 1.5-6-fold higher than those registered during the other epidemics under review. The higher morbidity resulted from the circulation during the 2011-2012 season of an A/Victoria/361/2011(H3N2)-like variant that presented a reduced genetic match with the A(H3N2) strain included in the 2011-2012 vaccine composition. The continuous surveillance of the characteristics of circulating viruses is an essential tool for monitoring their matching with seasonal vaccine strains. Strategies to increase coverage rates are warranted.