The genetic variability of influenza virus is usually studied with sequences selected over numerous years and countries, and rarely within a single season. Here we examined the viral evolution and the correlation between genetic and clinical features during an epidemic. From a French prospective household-based study in 1999-2000, 99 infected patients were randomly selected. The HA1 genomic domain was sequenced. Phylogenetic analysis showed the existence of two groups of A/H3N2 viruses. We found no distinct pattern of genomic evolution within either group according to time. A spatial correlation with the nucleotide distances was shown. The average nucleotide diversity was 3.4x10-3 nucleotides per site, and did not differ between the groups. A lower number of segregating sites was observed in patients who experienced influenza-like symptoms during the previous epidemic. These results suggest that the influenza virus undergoes regular HA1 nucleotide changes, but without clonal expansion of mutant strains within a single epidemic.