Molecules with immune modulating activity are ubiquitously distributed in nature and their impact on aquaculture has been exploited in order to increase fish resistance to pathogens. Here, we investigated the effect of inactivated Parapoxvirus ovis (iPPVO) on blood cells and innate and acquired immune response of silver catfish (Rhamdia quelen). iPPVO inoculation had no effect on respiratory burst activity; however, following iPPVO inoculation, we observed a significant decrease on circulating monocytes concomitantly with an increased number of heterophilic granulocytes and thrombocytes, which are the main cells involved in innate immunity and provide connection with acquired immunity. Fish inoculated with a combination of bovine serum albumin (BSA) + iPPVO had significantly higher levels of antibodies to BSA compared to fish inoculated with BSA alone, but lower than fish inoculated with BSA + Freund's incomplete adjuvant (FIA). These findings points to the potential usefulness of iPPVO as immunomodulator in fish and instigate further research to identify its component that interact with immune cells and that could be exploited as adjuvants in fish.