The contributions of mast cells to the pathology of allergic diseases, as well as to the expression of immunoglobulin E (IgE)-dependent host responses to parasites, reflect both the amounts and types of cytokines and other mediators that are released by these cells in such settings. Whereas mast cells cannot intrinsically express immunologically specific functions, the binding of IgE to high-affinity IgE receptors (Fc epsilonRI) on the surface of mast cells primes these cells to secrete cytokines and other biologically active products upon subsequent exposure to specific antigens. We now report that both HMC-1, a growth factor-independent human mast cell leukemia cell line, and growth factor-dependent human umbilical cord blood-derived mast cells can secrete the multifunctional C-C chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha). In addition, we found that in vitro exposure of human umbilical cord blood-derived mast cells to concentrations of IgE within the range observed in the serum of subjects with allergic diseases or parasite infections, which markedly up-regulates the ability of these cells to bind IgE to their surface, also significantly enhances the ability of the cells to secrete MIP-1alpha upon subsequent passive sensitization with IgE and challenge with anti-IgE. Thus, IgE-dependent enhancement of human mast cell IgE-binding ability permits these cells to respond to Fc epsilonRI-dependent challenge with significantly increased secretion of MIP-1alpha, a chemokine that can have diverse functions in inflammation, allergic reactions, and host responses to infection.