Most T cells in a normal non-immunized individual are in a resting state. However, a small proportion of splenic T cells are large activated cells both in specific pathogen-free and antigen-free mice. To further elucidate the effector functions associated with these "naturally" activated CD4+ T cells, we have characterized the expression of various membrane markers, cytokine production and T helper activity by these cells. We show that naturally activated CD4+ T cells express activation markers and contain tenfold higher proportions of cells producing IL-4, IL-10 and IFN-gamma as compared to small CD4+ T cells. Despite the high proportion of IFN-gamma producers, naturally activated CD4+ T cells still induce B cell proliferation and differentiation. These results are discussed in the context of normal physiological autoreactivity.