SIGNALLING for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T–B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein^2–5 with homology to tumour necrosis factor-α and -β^6,7, and has important functions in B-cell activation and differentiation^2,4,8. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized^9,10. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.