We have recently shown that CD45RA⁺CD4⁺ naive T cells can be activated to proliferate by a combination of IL-2, TNF-α and IL-6, but, at variance with TCR-medlated activation, they do not acquire the CD45RO molecule. This prompted us to investigate the phenotype of these cells and the functional features they display upon TCR stimulation. Naive T cells expanded by cytokines, though remaining CD45RA⁺ express a variety of activation and adhesion molecules which are peculiar to effector or memory T cells. Naive cells primed by cytokines, when activated with antl-CD3 mAb, produce a broad spectrum of cytokines, express CD40 ligand, but are unable to help B cells for Ig synthesis. A subset of CD4⁺CD45RA ⁺ RO^– T cells with a phenotype (HLA-DR^–, VLA-2⁺ or IL-2R⁺) similar to that of cells activated by cytokines In vitro can be found In vivo. These results demonstrate that activation signals delivered by cytokines, in the absence of TCR stimulation, can activate naive T cells to proliferate and differentiate into a ‘split phenotype’ with elements common to both naive and memory T cells. This novel antigen-Independent activation may help to maintain the naive T cell repertoire and facilitate the antigen-responsiveness of naive T cells.