Transplantation of tissues from other species has been advocated as a way to overcome the extreme shortage of human donors. Rejection, however, remains a major hurdle for clinical xenotransplantation. Although activation of macrophages by T cells is critical for the cellular rejection of xenografts, what other important interactions between these two types of cells remain less defined. When we activated macrophages of immuno-deficient mice (SCID or Rag-/-) using interferon-gamma and lipopolysacharide, xenogeneic cells were rejected by activated macrophages in the peritoneal cavity (which has an abundance of resident macrophages), but were not rejected under the kidney capsule (which requires the recruitment of effectors). This difference between the two sites implies that activated macrophages are inefficient for self-recruitment to peripheral graft sites and that T cells may still be required for the process. To test this hypothesis further, immunodeficient mice that had received xenogeneic cells were infused with peritoneal exudate cells (containing activated macrophages and activated T cells) from preimmunized immunocompetent mice. Xenogeneic cells at both the kidney capsule and peritoneal sites were rejected soon after cell transfer. However, when the exudate cells were transferred into SCID recipients that first had been injected with T cell depleting antibodies, xenograft rejection was only prominent at the peritoneal site but not kidney capsule site. These results argue that activated macrophages (as the result of T cell activation) still require T cells for xenograft rejection at peripheral sites.