HEp-2 cells that survived a lytic infection with Human Respiratory Syncytial Virus (HRSV) were grown to obtain a persistently infected culture that produced relatively high amounts of virus (106–107 pfu/ml) for more than twenty passages. The cells in this culture were heterogeneous with regard to the expression of viral antigens, ranging from high to undetectable levels. However, all cell clones derived from the persistent culture did not produce infectious virus or viral antigens and grew more slowly than the original uninfected HEp-2 cells. When these “cured” cell clones were infected with wild-type HRSV, delayed virus production and reduction in the number and size of syncytia were observed compared to lytically infected HEp-2 cells. Most significantly, differences in gene expression between persistently and lytically infected cultures were also observed, including genes that encode for cytokines, chemokines and other gene products that either promote cell survival or inhibit apoptosis. These results highlight the significantly different responses of the same cell type to HRSV infection depending on the outcome of such infection, i.e., lytic versus persistent.