Herpes simplex viruses infect a variety of cells in vitro. However, not all infected cells sustain a fully productive replication of these viruses. We have shown that, in U937 monocytoid cells, herpes simplex virus 2 (HSV-2) causes a low-productive infection characterized by apoptosis as cytopathic effect at a late stage of infection. This effect was associated with a down-regulation of the Bcl-2 protein. We therefore asked whether destabilization of Bcl-2 expression could act as a limiting factor for the productive HSV-2 infection. We found that overexpression of Bcl-2 in U937 cells dramatically increased the capability of these cells to sustain a fully productive infection, while protecting against apoptosis induced by HSV-2. Overall, our data indicate that Bcl-2 expression acts as a regulator of HSV-2 replication.