Calcium-sensitive spectrofluorometry was used to study the effects of endothelin on levels of intracellular calcium [Ca2+]i in cultured human microglia. Both ET-1 and ET-3 induced transient, non-desensitizing, increases in [Ca2+]i in over 80% of the cells studied. The responses to either ET-1 or ET-3 were significantly diminished in amplitude and duration in Ca2+-free solution suggesting a prominent contribution of Ca2+ influx to the response. ET-1 induced changes in [Ca2+]i were not altered in the presence of the selective ET(A) antagonist BQ610 but were significantly reduced with the selective ET(B) antagonist BQ780. These results confirm the expression of ET(B) receptors on human microglia, these receptors may serve a role in a signaling pathway between microglia and endothelial cells.