Replicating viruses generally induce type 1 immune responses, with high interferon (IFN)-gamma levels and antibodies of the IgG2a isotype. In the present study we demonstrate the intrinsic ability of non-replicating virions to induce comparable immune responses in the notable absence of any adjuvant. Injection of inactivated pseudorabies virus, an alphaherpesvirus, by various routes into mice resulted in the generation of T helper (Th) 1 type immune response. Co-delivery of inactivated pseudorabies herpesvirus (iPRV) with protein redirected IgG1-dominated tetanus toxoid-specific responses towards an IgG1/IgG2a balanced response. Also inactivated preparations of viruses from the paramyxo- (Newcastle disease virus), rhabdo- (rabies virus), corona- (infectious bronchitis virus) and reovirus (avian reovirus) families led to IgG2a antibody responses; however, the genetic background of the host did result in considerable variation. Because disrupted virions also induced type 1 immune responses, we conclude that structural elements of virions inherently contribute to IFN-gamma-dependent isotype switching by inactivated viruses. Strikingly, immunizations in gene-disrupted mice showed that a functional IFN-alpha/beta, IFN-gamma or interleukin (IL)-12 pathway was not required for the generation of a polarized Th1 type immune response initiated by inactivated virus particles. These findings have a bearing on the understanding of immune responsiveness to virus structures and the design of vaccines containing virus components.