Apolipoprotein E (ApoE) is synthesized by a variety of cells including macrophages. These cells activate T lymphocytes by antigen presentation, while the T‐cell cytokine, interferon‐γ, inhibits macrophage ApoE expression. ApoE inhibits T‐cell proliferation in culture but its role in immune responses has been unclear. The ApoE‐deficient (E⁰) mouse permits an evaluation of the immunological role of ApoE. We have analysed T‐cell responses to an exogenous antigen (ovalbumin) and polyclonal mitogen (concanavalin A) in E⁰ and ApoE^+/+ mice. Macrophages of E⁰ mice stimulated T‐cell activation more effectively as antigen‐presenting cells than macrophages from ApoE^+/+ mice. Both proliferation and interferon‐γ secretion were enhanced in T cells activated in the context of antigen‐presenting cells from E⁰ mice. Since the macrophage–T‐cell interaction depends on interactions between cell surface molecules, we assessed the expression of such molecules after in vivo stimulation with interferon‐γ. This treatment caused an increased expression of the co‐stimulatory surface proteins CD40 and CD80, and also of the major histocompatibility complex class II molecules I‐A^b on macrophages of E⁰ mice compared with ApoE^+/+. Our data suggest that ApoE inhibits T‐cell activation by reducing the density of immune stimulatory proteins on antigen‐presenting cells.