The release of regulated on activation normal T-cell expressed and secreted (RANTES) from CD8+ lymphocytes has been shown to be dependent on T-cell receptor triggering by major histocompatability complex class I/peptide complex engagement. We characterized the secretion of RANTES by human leukocyte antigen-A2-restricted tyrosinase-specific cytotoxic T lymphocyte (CTL) in the context of human melanoma cell killing. CTL contact with tumor cell targets elicited a vectorial release of the chemokine RANTES resulting in the selective deposition of RANTES on target cells but not on nontarget bystander cells or the CTL. RANTES on the surface of apoptotic cells enhanced their phagocytosis by murine macrophages. This effect appeared unique to RANTES as the related chemokines macrophage inflammatory protein (MIP) -1alpha, MIP-1beta, and monocyte chemoattractant protein-1 did not significantly affect uptake and were mediated through chemokine receptor CCR1. Oligomerization of RANTES, at least at the level of a tetramer, was required for the enhanced phagocytosis. These results suggest that the role of RANTES in inflammatory disorders might not be restricted to inducing leukocyte infiltration but could also extend to potent macrophage modulation, directly regulating inflammation.