Influenza is a major worldwide respiratory pathogen responsible for seasonal epidemics and occasional worldwide pandemics. Influenza infection can lead to an accumulation of fluid in the respiratory tract, implying that the virus can modulate the ion transport in these tissues. Previous work has shown influenza infection acutely modulates Na⁺ absorption by inhibiting the epithelial sodium channel (ENaC) (Kunzelmann et al. 2000). Recent work has shown that influenza A NS1 protein can activate host cell intracellular phosphatidylinositol-3-kinase (PI3K) (Hale et al. 2006). Since this enzyme is involved in the regulation of ENaC expression, we have examined the effect of NS1 expression on Na⁺ conductance (G_Na) in the H441 human bronchiolar cell model. G_Na in H441 cells grown in hormone free conditions is negligible, but can be stimulated by treatment with the glucocorticoid hormone dexamathasone (Clunes et al. 2004). Here we report a G_Na recorded from voltage clamped H441 human epithelial cells stimulated by the transfection of influenza A NS1 protein. In control, hormone free, cells (GFP only) the resting membrane potential (V_m, -61.7 ± 2.4 mV) was unaltered by lowering external sodium. Expression of NS1 depolarized V_m to -22 ± 2.2 mV. Lowering [Na⁺]_o to 10 mM hyperpolarized this V_m to -43.1 ± 2.6 mV indicating that G_Na is significant. Analysis of the external sodium-dependant component of the membrane current indicated an NS1 induced G_Na of 455 ± 165 pS/cell. Expression of NS1-Y89F, a mutant unable to activate 3-phosphatidylinositol phosphate kinase (PI3K) (Hale et al. 2006), also induced G_Na of magnitude 258 ± 53 pS cell 1 which was smaller (P < 0.05) than in cells expressing wild type NS1. Expression of NS1-Y89F in combination with membrane-anchored PI3K P110a subunit induced G_Na of magnitude 458 ± 158 pS/cell thus recovering the response of WT-NS1. NS1 expression can therefore mimic the effect of glucocorticoid stimulation by inducing G_Na and ~50% of this response can be attributed to an effect upon PI3K.