Background.?Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence as the primary target cells of other influenza viruses have not been systematically studied.Methods.?We provide the first comparison of the replication, tropism and cytokine induction of human, highly pathogenic avian H5N1 and other animal influenza A viruses in primary human lung organ cultures.Results.?H5N1 and human-adapted H1N1 and H3N2 viruses replicated efficiently in the lung tissue, whereas classical swine and low pathogenic avian viruses propagated only poorly. Nevertheless, all viruses examined were detected almost exclusively in type II pneumocytes with a minor involvement of alveolar macrophages. Infection with low- and highly pathogenic avian viruses provoked a pronounced cyto- and chemokine induction while human and pandemic H1N1-2009 viruses triggered only weak responses.Conclusions.?These findings show that differences in the pathogenic potential of influenza A viruses in the human lung cannot be attributed to a distinct cellular tropism. Rather, high or low viral pathogenicity is associated with a strain-specific capacity to productively replicate in type II pneumocytes and to cope with the induced cytokine response.