S100A4 is a Ca 2+ -binding protein that performs an important role in metastasis. It is also known for its antitumor functions. S100A4 is expressed by a specialized subset of CD 4+ CD 25+ lymphocytes and is present on those cell's membranes along with peptidoglycan recognition proteins (PGRPs). There, by interacting with major heat shock protein Hsp70, S100A4 plays an important cytotoxic role. The resulting stably formed complex of PGRPs, S100A4 and Hsp70 is required for the identification and binding between a lymphocyte and a target cell. Here, we investigated the S100A4 functions in CD 4+ CD 25+ PGRPs + S100A4 + lymphocyte cytotoxicity against target cells. We demonstrated that those lymphocytes do not form a stable complex with the tumor target cells that themselves have S1004A on their surface. That observation can be explained by our finding that S100A4 precludes the formation of a stable complex between PGRPs, S100A4 (on the lymphocytes’ surface), and Hsp70 (on the target cells’ surface). The decrease in S100A4 level in CD 4+ CD 25+ PGRPs + S100A4 + lymphocytes inhibits their cytotoxic activity, while the addition of S100A4 in the medium restores it. Thus, the resistance of target cells to CD 4+ CD 25+ PGRPs + S100A4 + lymphocyte cytotoxicity depends on their S100A4 expression level and can be countered by S100A4 antibodies.