Interleukin (IL)-4 and IL-10 have a wide variety of activities in the immune system. We re-evaluated the action of IL-4 and IL-10 on human blood monocytes, myeloid dendritic cell (DC1) precursors, using a serum-free culture system. Both IL-4 and IL-10 inhibited the survival of CD14+ monocytes supported by granulocyte-macrophage colony-stimulating factor in a dose-dependent manner. When IL-4 and IL-10 were combined, they had synergistic effects at low doses and induced a profound suppression of CD14+ monocyte survival. When the optimal timing was determined, the exposure to IL-4 and IL-10 for the initial 2 days was essential for suppression of survival of CD14+ monocytes. Annexin V/propidium iodide staining indicates that the suppression of CD14+ monocyte survival induced by IL-4 and IL-10 results from apoptosis. Tumor necrosis factor-alpha and lipopolysaccharide abrogated the effects of IL-4 and IL-10 on CD14+ monocytes, albeit incompletely. Thus, IL-4 in synergy with IL-10 negatively regulates the survival of DC1 precursor monocytes by inducing their apoptosis, which is modulated by factors such as tumor necrosis factor-alpha and lipopolysaccharide. Our data suggest the primary activities of IL-4 and IL-10 in DC1-mediated immune responses.