Hyper-IgM syndrome is an inherited regulatory defect in Ig isotype switching due in many cases to the absence of CD40 ligand on activated T lymphocytes and is manifested by normal to elevated levels of serum IgM but decreased IgG and IgA. Hyper-IgM patients also frequently suffer from chronic, severe neutropenia and recurrent infections, most often sinopulmonary in nature. We present a 14 year old male with markedly elevated serum IgM and IgA but low serum IgG and IgE who has also suffered from profound chronic neutropenia. In addition to recurrent sinopulmonary infections, he has previously developed Cryptococcal meningitis, severe oral ulcers complicated by Pseudomonas osteomyelitis, and esophageal ulcers complicated by stricture formation. Analysis of activated T cells revealed the presence of CD40 ligand, and EBV-transformed 8 cells expressed CD40 normally. Proliferative responses of peripheral blood mononuclear cells were normal to PMA/ionomycin but markedly depressed to PHA or anti-CD3 stimulation. Bone marrow aspirate revealed arrested myeloid development at the promyelocyte stage. There was no neutrophil response to infusions of G-CSF or GM-CSF. Following two separate granulocyte infusions, with starting granulocyte numbers less than 100/mm3, the patient responded each time with a rise in peripheral granulocyte counts, perceptible at 7 days, to over 3,000/mm3 at 11 days post-infusion, then returning to pre-infusion levels. We speculate that this patient has a defect in the regulation of cytokine production or of a receptor subunit which may affect not only myeloid differentiation but also Ig isotype switching.