During the 2002/2003 season, Italian sentinel-based network for surveillance of influenza, coordinated by Inter-university (Genoa-Milan-Trieste) Centre for Influenza Research (CIRI) registered an increasing incidence from week 9/2003 (10.3 cases per 1000). The epidemic curve highlighted different incidences in the three ages group: morbidity rate was higher in children (24.4 cases/1000, at week 9/2003) than in adults (8.8 cases/1000) and in >65 year group (5.1 cases/1000) in which high vaccination coverage was reached. It is noteworthy that, in this age group, laboratory-confirmed cases in immunized subjects and outbreaks in nursing homes where the vaccine coverage is close to 100% were registered. The rapid increase of influenza activity was characterized by the co-circulation of A/H3N2/Toulouse/878/01-like viruses, similar to the vaccine strain A/Moscow/10/99, and new strains that have different antigenic properties with respect to the H3N2 vaccine strain and the major 2001/02 epidemic A/H3N2 strains (A/Panama/2007/99 and A/Toulouse/878/01). The results of HI test showed that viruses isolated in Northern Italy gave reduced titres with antisera to vaccine strain and recent reference strains. Molecular characterization of the gene HA allowed the identification of new variants belonging to the cluster clearly separated from the strains circulated in the previous seasons. The new sequences are similar to that of A/HongKong/1143/02, previously isolated in Asia and USA and not yet circulating in Europe. At least two amino acid changes were observed over A, B, D, and E antigenic sites and 1–2 over C site relative to A/Moscow10/99. These substitutions suggest the possibility of sub-optimal protection of the A/H3N2 component in immunised subjects. Considering these molecular data and the HI test findings, the new variant isolates in Northern Italy might escape from the immunological pressure induced by vaccination and previous infections, representing the potentially epidemic strain.