Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor α (TNF-α) was reported by some to have pro-apoptotic and by others to have anti-apoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF-α at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF-α lost its protective effects, and also reversed the protective effects of interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This pro-apoptotic effect of TNF-α was blocked by anti-CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF-α retained its anti-apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN-γ, GM-CSF, and TNF-α itself are overruled when the concentration of TNF-α is high enough to produce a respiratory burst. These dual, concentration-dependent effects of TNF-α provide an explanation for previous controversial reports and support a dominant role for TNF-α in neutrophil apoptosis.