CD4 T cell activation requires stable contact with APCs. In the present study we demonstrate that anti-CD3-stimulated memory but not naive CD4 T cells fail to form stable conjugates with MHC class II+ APCs and fail to become activated. Early deconjugation by memory CD4 T cells is dependent on CD4-MHC class II interactions in that conjugation is restored when the APC do not express MHC class II or when the class II molecule is mutated at the CD4 binding site. Furthermore, MHC class II-restricted memory-T cells from CD4-deficient mice form stable conjugates, indicating that the CD4 molecule expressed on naive and memory CD4 T cells differs in function and regulates memory but not naive CD4 T cell adhesion to syngeneic APCs in the absence of Ag. This mechanism may have implications for Ag-primed memory CD4 T cells in that primed memory cells, which express an increased number of adhesion molecules, may dissociate from cells in the absence of CD4/TCR co-ligation by the same MHC class II molecule. This would prevent bystander activation and assure efficient recirculation of activated memory T cells in search of Ag-bearing target cells.