The apoptosis of bone marrow-derived mast-cells (BMMCs) after growth factor withdrawal was significantly prevented by a high concentration of IgE in the absence of antigen, and further enhanced by the presence of Toll-like receptor4 (TLR4) ligand, lipopolysaccharide (LPS). The effect of LPS was mediated by TLR4, since TLR4-deficient BMMCs did not show synergistic effects with IgE. The neutralizing amount of anti-IL-3 did not reverse the anti-apoptotic effects of both IgE and combination with LPS. LPS treatment with monomeric IgE synergistically prevented the loss of mitochondrial membrane potentials and was associated with an enhanced expression of anti-apoptotic protein, Bcl-xL, or with a reduced expression of proapoptotic protein, Puma, and Bim, respectively. Altogether, these results suggest that LPS, in a TLR4-dependent manner, together with IgE, synergistically prevent mast-cell apoptosis and may contribute to regulate the tissue mast-cell number.