The activity and circulation of influenza viruses in Lombardy — Northern Italy — (a region with nearly 10 out of the 60 million inhabitants of Italy) were investigated during two consecutive seasons (2010–2011 and 2011–2012), as part of the Italian Influenza Surveillance Network. The molecular characteristics of the hemagglutinin (HA) sequence of circulating viruses were analyzed to investigate the emergence of influenza viral variants. In the surveyed area, the influenza activity of these two post-pandemic seasons was similar in terms of both time frame and impact. The timing of the influenza epidemics was similar to the timing seen prior to the emergence of the pandemic A(H1N1) virus in 2009. A(H1N1)pdm09 was the predominant virus circulating during the 2010–2011 post-pandemic season and then—unexpectedly—almost disappeared. The HA sequences of these A(H1N1)pdm09 viruses segregated in a different genetic group with respect to those identified during the 2009 pandemic, although they were still closely related to the vaccine viral strain A/California/07/2009. Influenza A(H3N2) viruses were the predominant viruses circulating during the 2011–2012 season, accounting for nearly 88% of influenza viruses identified. All HA sequences of the A(H3N2) viruses isolated in the 2011–2012 season fell into the A/Victoria/208/2009 genetic clade (although the A/Perth/16/2009 virus was the reference vaccine strain). B viruses presented with a mixed circulation of viral variants during these two seasons: viruses belonging to both B/Victoria and B/Yamagata lineages co-circulated in different proportions, with a notable rise in the proportion of B/Yamagata viruses (B/Wisconsin/1/2010-like) during the 2011–2012 epidemic. In conclusion, the continuous monitoring of the characteristics of circulating viruses is an essential tool for understanding the epidemiological and virological features of influenza viruses, for monitoring their matching with seasonal vaccine strains, and for tuning vaccination strategies.