As shown in a number of species, susceptibility to infectious diseases can be efficiently reduced following application of inactivated parapox ovis viruses (iPPOV). However, the basic mechanism for this stimulating capacity of iPPOV remains unclear. When analyzed, the interaction of iPPOV with porcine peripheral blood mononuclear cells was seen to involve T helper cells as the main target cell population responding to iPPOV. These cells displayed a strong proliferation, and were the major source for the observed increased levels of IL-2. Activation of the T helper cells was MHC class II dependent, but not MHC class II restricted: cellular processing of iPPOV was not required for presentation by autologous, allogeneic or xenogeneic MHC class II molecules. Furthermore, CD3 and CD4 molecules were involved in the stimulation, indicating a receptor-mediated activation of T helper cells. The results demonstrated typical characteristics of a superantigen-induced response providing evidence for a viral component within PPOV functioning as superantigen(s) in swine.