Stimulation of macrophages via CD40 promotes their classical activation. Therefore, CD154 (CD40 ligand) can be expected to oppose macrophage polarization and proliferation induced by IL-4. However, there is limited experimental data to support this, which is additionally complicated by the possibility of differential effects of CD40 agonists in different formats/contexts. Whereas canonically CD4+ T cells upregulate CD154 strongly following exposure to cognate antigen, naïve CD4+ cells constitutively express significant levels of CD154, which could be a tonic signal. Soluble CD154 and agonistic CD40 antibodies also trigger CD40 signaling. We explored these questions in a reductionist model of IL-4 delivery to mouse peritoneal cavity cells in vitro and in vivo. Soluble CD40 agonists inhibited M(IL-4) polarization, with a stronger effect on RELMa than on Ym1 (Chil3), as well as inhibiting IL-4 induced proliferation. CD154 provided by CD4+ cells in the context of an antigen-specific interaction blunted macrophage RELM-a expression but did not affect Ym1. Macrophages negatively regulated, via CD40, constitutive cell-surface CD154 on naïve CD4+ cells, both in vitro and in vivo. The large peritoneal macrophages of CD40 KO mice showed a moderately enhanced RELMa response to IL-4, but this was not a cell-autonomous effect. No differences between WT and CD40 KO mice were detected in IL-4-induced macrophage proliferation. We conclude that strong CD40 stimulation, included stimulation by CD154 expressed by antigen-specific CD4+ cells, blunts selected macrophage responses to IL-4, and that constitutive CD4+-cell CD154, in spite of interacting with CD40 on macrophages, does not directly influence macrophage responses to IL-4.