To elucidate the mechanism of human cell elimination from severe combined immunodeficient (SCID) mice transplanted with human peripheral blood lymphocytes (hu‐PBL‐SCID mice), we explored the immunocytes in the peritoneal cavity in SCID mice where human PBL were transferred. When the phenotype of peritoneal exudate cells (PEC) was compared by flow cytometry among three congenic strains of SCID mice that differ in their acceptability for human PBL, the PEC in NOD‐scid mice, which exhibit the highest acceptability, contained the smallest number of F4/80^lo/−Mac‐1⁺‐activated macrophages. Moreover, the proportions of natural killer cells in PEC of the three strains of SCID mice were not always correlated with the acceptability. These findings suggest the possibility that peritoneal macrophages eliminate human cells in hu‐PBL‐SCID mice. To verify this hypothesis, we evaluated the engraftment of human PBL into SCID mice that were treated with liposome‐encapsulated dichloromethylene diphosphonate, which selectively depletes macrophages by inducing apoptosis, or 8‐aminoguanidine hemisulphate salt, an inhibitor of inducible nitric oxide synthase of macrophages. As a result, both of these regimens improved engraftment of human PBL, indicating that peritoneal macrophages take part in human cell elimination in the peritoneal cavity of hu‐PBL‐SCID mice and that it is mediated, at least in part, by direct macrophage cytotoxicity utilizing nitric oxide.