Sheep-associated malignant catarrhal fever (MCF), caused by Ovine herpesvirus 2 (OvHV-2), is a usually fatal disease of various ruminants and swine. A system for propagation of OvHV-2 in vitro has not yet been identified, although persistently infected cells have been derived from diseased animals and used to establish an animal model in rabbits. OvHV-2 structural proteins have not been detected in diseased animals and the pathogenesis of OvHV-2 infection is poorly understood. Recently, the genomic sequence of OvHV-2 has been determined, which allowed to predict the amino acid sequences of putative OvHV-2 structural proteins. Based on those predictions, we have generated antisera against two putative structural proteins (ORF43 and ORF63) of OvHV-2 in order to detect sites of active virus replication in experimentally OvHV-2-infected rabbits with signs of MCF. Although histological lesions typical of MCF were detected in multiple tissues, those sera detected viral capsid and tegument antigens exclusively in the appendix but not in other tissues of rabbits with MCF. More specifically, those viral proteins were detected in epithelial cells as well as in M-cells. However, in situ hybridization revealed that ORF63 mRNA was present in epithelial cells of infected rabbits but not in M-cells. Our data suggest that active OvHV-2 replication takes place in certain tissues of animals with MCF and that M-cells may play a role in the pathogenesis of MCF.