Various human diseases are associated with gammaherpesvirus infections, including neoplasms of lymphocytes (e.g. Burkitt's lymphoma) and endothelial cells (e.g. Kaposi's sarcoma). Gammaherpesvirus infection of cells usually results in either productive infection that is characterized by new virus production and rapid destruction of the host cell, or latent infection that is characterized by long-term carriage of viral DNA in intact cells that do not produce virus. Here, we characterize endothelial cell infection using a small animal model of gammaherpesvirus infection and disease. While infection of endothelial cells resulted in virus production as most cells do, infection of this cell type was unique in that cells remained intact and continued to proliferate. These intact, infected endothelial cells were significantly altered in appearance and gene expression compared to uninfected cells, changes predicted to impact endothelial cell growth and function. Endothelial cells were unique in their ability to support this type of persistent infection. These data demonstrate an additional mechanism, beyond latency, by which gammaherpesviruses may achieve long-term propagation, particularly in conditions of immune suppression. Our results suggest persistently infected cells as a therapeutic target for prevention/ treatment of chronic disease, and may provide a mouse model for future testing.