In 2002, prior to the generalization of zanamivir and oseltamivir utilization in France, we had decided to test a large panel of influenza strains to establish the baseline sensitivity of these viruses to anti-neuraminidase drugs. Since 2002, routine monitoring of resistance relies mainly on the results of neuraminidase enzyme assay. The profile of sensitivity of A/H3N2 viruses has not changed during these three influenza seasons. Neuraminidase N2 was shown to be more sensitive to oseltamivir carboxylate than to zanamivir. Amongst 788 viruses tested, only 10 were found with outliers IC(50) values (seven in 2003, one in 2004, and two in 2005). After the sequencing of the neuraminidase segment of these viruses, seven mutations on the stalk or the head of the glycoprotein (A18S, L23F, C42R, R143V, E199K, S332K, R431N) were detected. Moreover during seasons 2003-2005, 12 additional viruses were characterized by a complete lack of neuraminidase activity. In these viruses, viral resistance to NA inhibitors can be related with the presence of a defective neuraminidase RNA segment as evaluated by a plaque reduction assay, these viruses having a reduced dependence on its neuraminidase activity.