Experiments were performed to characterize and identify the cellular sources of the secondary interleukin (IL)-4 response to a T cell–dependent antigen. Mice were primed by immunization with goat anti–mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4⁺ T cells to secrete IL-4 in 3–4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by ∼100-fold, started in <2 h, and lasted for 4 d. Studies with 4get mice, in which cells with an accessible Il4 gene express a green fluorescent protein (GFP), revealed CD4⁺ memory T cells, natural killer T cells, basophils, mast cells, and eosinophils as possible rapid producers of IL-4. GFP⁺CD4⁺ T cells and basophils expanded more in the spleen than the other cell types during the primary response to GaMD. Quantitation of in vivo IL-4 production by the in vivo cytokine capture assay after individual cell types were selectively stimulated or deleted demonstrated that basophils and memory CD4⁺ T cells account for most of the secondary IL-4 response, with basophils initiating that response through IgE/FcεRI-mediated signaling but secreting IL-4 for <4 h and memory T cells secreting IL-4 within 4 h and continuing to secrete this cytokine for 4 d.