It was previously shown that costimulation of CD8+ lymphocytes results in de novo expression of CD4. This study expanded on this observation to investigate the function of CD4 on CD8 cells. The ability of costimulated CD8 cells to respond to interleukin 16 (IL-16), a ligand that binds CD4 and induces cellular chemotaxis, was examined. IL-16–mediated ligation of CD4 expressed on CD8 T cells was found to induce an intracellular signal that directs migration of these cells in vitro. Thus, expression of CD4 on a CD8 lymphocyte has functional importance and may serve to control distribution of newly activated CD8 T cells in vivo.