Memory or antigen-experienced CD4 T cells differ from naive CD4 T cells both phenotypically by cell surface marker expression, and functionally by their dissimilar pattern of cytokine secretion and activation requirements through their T cell receptor (TCR). We show here that activation of memory CD4 T cells (CD45RBlo subset), but not naive CD4 T cells (CD45RBhi subset), is inhibited by MHC class II molecules on antigen-presenting cells and by CD4 ligation. We propose that the selective negative signal in memory cells is a direct result of the differences in signaling via CD4 and CD3, exemplified in the disparate pattern of tyrosine-phosphorylated proteins visible after activation of the two subsets. In vivo, this inhibitory signal may serve to prevent irrelevant interactions between memory CD4 T cells and bystander MHC class II+ cells, and may also be responsible for the defective functioning of memory CD4 T cells in AIDS.