Orf virus (ORFV) has been demonstrated to infect both goat non-immune cells, specifically goat epithelial cells, and goat blood immune cells. Our previous studies have indicated that ORFV gains entry into goat epithelial cells via clathrin-mediated endocytosis and macropinocytosis pathways. However, the pathway by which ORFV enters goat blood immune cells has not yet been elucidated. Our findings revealed a differential viral internalization pathway in ORFV-infects goat immune cells contrasting the internalization pathways in goat epithelial cells, potentially involving an antibody-related mechanism. Therefore, our hypothesis posits that ORFV gains entry into goat immune cells via the antibody-dependent enhancement (ADE) pathway. Our experimental findings confirm the presence of the ADE effect in ORFV-infected goat immune cells, mediated by Fc receptors (FcRs) as demonstrated in antibody-blocking experiments. Furthermore, the ADE effect was also observed in goat epithelial cells. Nevertheless, the ADE effect observed in goat epithelial cells was not found to be dependent on the interaction between the virus-antibody complex and Fc receptors, as demonstrated by antibody-blocking experiments. Instead, it is suggested that an alternative mechanism involving the complement factor and complement receptors (CRs) may be responsible. Overall, this research offers insights into the unique ADE pathway of ORFV infection in different cell types, offering a novel perspective on the infection and pathogenic mechanisms of ORFV.