Glycoinositolphospholipids (GIPLs) are some of the major glycolipids of the Trypanosoma cruzi surface that were previously shown to activate B cells. In the present study, we investigated whether (i) T. cruzi GIPLs could induce immunoglobulin secretion from B cells in the absence of T cells and NK cells and whether (ii) NK cells are also stimulated by the GIPLs. B cells purified from mice deficient in both T and NK cells (CD3epsilon transgenic mice) secreted immunoglobulin in response to the GIPL. This response was increased by coculture with a murine NK cell line. The T. cruzi GIPL also increased the NK cell (interleukin-2 induced) proliferative response. Our data indicate that the T. cruzi GIPL has a direct stimulatory effect on NK cells and induces immunoglobulin secretion in the absence of T lymphocytes and NK cells. These findings suggest that this T. cruzi-derived molecule may be one of the stimulators that lead to NK cell activation during T. cruzi infection.