Influenza viruses continue to present global threats to human health. Antigenic drift and shift, genetic reassortment, and cross-species transmission generate new strains with differences in epidemiology and clinical severity. We compared the temporal transcriptional responses of human dendritic cells (DC) to infection with two pandemic (A/Brevig Mission/1/1918, A/California/4/09) and two seasonal (A/New Caledonia/20/99, A/Texas/36/1991) H1N1 influenza viruses. Strain-specific response differences included stronger activation of NFκB following infection with A/New Caledonia/20/99 and a unique cluster of genes expressed following infection with A/Brevig Mission/1/1918. A common anti-viral program showing strain-specific timing was identified in the early DC response and found to correspond with reported transcript changes in blood during symptomatic human influenza infection. Comparison of the global response to the seasonal and pandemic strains showed that a dramatic divergence occurred after 4 h, with only the seasonal strains inducing widespread mRNA loss.