Background: The recent emergence of the H5N1 influenza virus from avian reservoirs has raised concern about future influenza strains of high virulence emerging that could easily infect humans. We analyzed differential gene expression of lung epithelial cells to compare the response to H5N1 infection with a more benign infection with Respiratory Syncytial Virus (RSV). These gene expression data are then used as seeds to find important nodes by using a novel combination of the Gene Ontology database and the Human Network of gene interactions. Additional analysis of the data is conducted by training support vector machines (SVM) with the data and examining the orientations of the optimal hyperplanes generated.Results: Analysis of gene clustering in the Gene Ontology shows no significant clustering of genes unique to H5N1 response at 8 hours post infection. At 24 hours post infection, however, a number of significant gene clusters are found for nodes representing "immune response" and "response to virus" terms. There were no significant clusters of genes in the Gene Ontology for the control (Mock) or RSV experiments that were unique relative to the H5N1 response. The genes found to be most important in distinguishing H5N1 infected cells from the controls using SVM showed a large degree of overlap with the list of significantly regulated genes. However, though none of these genes were members of the GO clusters found to be significant.Conclusions: Characteristics of H5N1 infection compared to RSV infection show several immune response factors that are specific for each of these infections. These include faster timescales within the cell as well as a more focused activation of immunity factors. Many of the genes that are found to be significantly expressed in H5N1 response relative to the control experiments are not found to cluster significantly in the Gene Ontology. These genes are, however, often closely linked to the clustered genes through the Human Network. This may suggest the need for more diverse annotations of these genes and verification of their action in immune response. © 2010 Tatebe et al; licensee BioMed Central Ltd.