T CELLS express T-cell antigen receptors (TCR) for the recognition of antigen in conjunction with the products of the major histocompatibility complex^1,2. They also express two key surface coreceptors, CD4 and CDS, which are involved in the interaction with their ligands^3,4. As CD4 is expressed on the early haemopoietic progenitor⁵ as well as the early thymic precursor cells⁶, a role for CD4 in haemopoiesis and T-cell development is implicated. Thymocytes undergo a series of differentiation⁷ and selection steps^8,9 to become mature CD4⁺8⁻ or CD4⁻8⁺ (single positive) T cells^10,11. Studies of the role of CD4⁺ T cells in vivo have been based on adoptive transfer of selected or depleted lymphocytes, or in vivo treatment of thymectomized mice with monoclonal antibodies causing depletion of CD4⁺ T cells^12–14. In order to study the role of the CD4 molecule in the development and function of lymphocytes, we have disrupted the CD4 gene in embryonic stem cells^15–16 by homologous recombination^17–18. Germ-line transmission^19–20 of the mutation produces mutant mouse strains that do not express CD4 on the cell surface. In these mice, the development of CD8⁺ T cells and myeloid components is unaltered, indicating that expression of CD4 on progenitor cells and CD4⁺ CD8⁺ (double positive) thymocytes is not obligatory. Here we report that these mice have markedly decreased helper cell activity for antibody responses, although cytotoxic T-cell activity against viruses is in the normal range. This differential requirement for CD4⁺ helper T cells is important to our understanding of immune disorders, including AIDS, in which CD4⁺ cells are reduced or absent.