Drosophila hemocytes have strong phagocytic capacities and produce antimicrobial peptides (AMPs). However, the precise role of blood cells during immune responses and developmental processes has only been studied using indirect means. To overcome this limitation, we generated plasmatocyte-depleted flies by specifically overexpressing the proapoptotic protein Hid into plasmatocytes. Unexpectedly, these plasmatocyte-depleted animals have a normal larval and pupal development and do not exhibit any obvious defect after birth. Remarkably, plasmatocyte-depleted adults show a strong susceptibility to infections by various microorganisms, although activation of systemic AMP gene transcription via the Toll and immune deficiency (IMD) pathways is wild-type. Our data show that this susceptibility, which correlates with overproliferation of bacteria, is likely due to the absence of phagocytosis. We also demonstrate that during larval stages, plasmatocytes play an essential role in mediating AMP production by the fat body after oral bacterial infection. Finally, we show that plasmatocytes are involved in immune surveillance during pupal development, because they prevent bacterial infection that causes pupal lethality.