The cellular source of IFN alpha after induction with Herpes simplex virus type-1 (HSV) and HSV-infected fibroblasts was investigated by using human peripheral blood mononuclear cell (PBMC) populations, purified according to conventional procedures, and which included T- and B-lymphocytes as well as monocytes. It appears that the cells responding to HSV virions are monocytes, whereas the PBMC population induced by HSV-infected cells is represented by B-lymphocytes. Furthermore, by using monoclonal antibody (MoAb) to HLA class I and class II products, it appears that different membrane structures are involved in the induction of IFN by HSV virions, as opposed to HSV-infected cells. In fact, most anti-HLA class II MoAbs inhibit IFN induction by HSV-infected cells, and not IFN induction by HSV virions.