The CD4 molecule is a receptor found on a subset of T lymphocytes. It has been proposed that, upon binding MHC class II molecules expressed on APC, the CD4 molecule enhances the responsiveness of the T cell by increasing intercellular avidity and/or by transducing an intracellular signal. We have analyzed the effect of removing the cytoplasmic domain of the CD4 molecule on the ability of the CD4 molecule to enhance T cell responsiveness. The cytoplasmic domain-deleted mutant of the CD4 molecule (CD4Δ) was found to be as efficient as the CD4 molecule at enhancing responsiveness to cells bearing the appropriate Ag. If subcellular Ag in the form of purified Ag incorporated into liposomes was used, the CD4 molecule was found to be much more efficient than the CD4Δ molecule at enhancing responsiveness. However, the defect in the ability of the CD4Δ molecule to enhance responsiveness could be compensated for by increasing the level of expression of the CD4Δ molecule.