The interleukin (IL)-15-dependent immune responses of murine microglia were strongly affected by low concentrations of the ganglioside GD3. The ganglioside binding to IL-15 inhibited the proinflammatory effects of the cytokine, reducing IL-15-dependent T-cell proliferation as well as mRNA expression for IL-15Ralpha, p65, and NFATc2 in the N13 murine microglial cell line. Treatment of primary murine microglial cultures with GD3 abolished IL-15 production, without affecting cellular viability, but decreased the production of nitric oxide, a direct sensor of inflammation and nuclear factor-kappaB activity. We conclude that low doses of GD3 could inhibit specific proinflammatory mechanisms and modulate the inflammatory environment, leading to a less reactive scene. Microglial cells are one of the main actors in the inflammatory events that follow CNS trauma or an autoimmune disease episode, modulating the internal production of cytokines, growth factors, and other homeostatic molecules that may determine the evolution and outcome of tissue damage. Proinflammatory cytokines have a relevant role in the initial events, and modulation of their activity by gangliosides could cut down their harmful effects and interfere with invasion of the CNS by peripheral immune cells. The antiinflammatory properties of GD3 could be significant in the treatment of pain subsequent to CNS damage.