Phagocytic cells function as pathogen sensors. Macrophages and neutrophils provide the first line of defense following infections. Macrophages and dendritic cells are antigen presenting cells and play a crucial role in the establishment of the adaptive immune response. Infection with RVFV-GFP showed that phagocytic cells are also target cells for RVFV. We investigated the importance of the in vivo interaction between phagocytic cells and RVFV. We treated Ifnar1-deficient 129S2/SvPas mice with CLL to deplete the population of phagocytic cells, and showed that, following intradermal infection with RVFV, the depleted mice allowed reduced RVFV replication compared to control mice, as assessed both by in vivo imaging and viral titration from blood samples. Accordingly, CLL-treated mice displayed enhanced survival time compared with control mice, indicating that phagocytic cells are involved in the pathogenesis of RVF. Altogether, our data suggest that during the initial stages of infection of Ifnar1 2/2 mice, the virus replicates inside macrophages and dendritic cells. On the other hand, since the RVFV replicates in diverse cell types in peripheral tissues, the infection may progress rapidly and lead to acute hepatitis and death.