Immunodeficiency with hyper-IgM (HIM) is a rare disorder characterized by recurrent infections associated with low IgG and IgA, and normal to increased IgM serum levels. Both primary and secondary forms of HIM syndrome have been reported. Among primary HIM syndrome, evidence for genetic heterogeneity is provided by the occurrence of the disease as X-linked, autosomal recessive, or autosomal dominant trait. The most common clinical manifestations include upper and lower respiratory tract infections, otitis, diarrhoea, oral ulcers, lymphoid hyperplasia, and autoimmunity. Recurrent neutropaenia is a frequent finding. Immunological abnormalities consist of lack of IgG and IgA secretion, and failure to respond to vaccination. Lymph nodes show absence of germinal centres. Few patients with a concurrent T-cell defect, and clinical expression of combined immune deficiency, have been reported. The gene responsible for the X-linked HIM syndrome (HIGM1) has been tentatively assigned to Xq24-27. However, carrier detection and prenatal diagnosis are not yet possible. Pathogenetic hypotheses include failure of B-cell differentiation, and defective regulation of immunoglobulin isotype switching due to abnormal T-cell-mediated signals. Treatment is mainly based upon regular administration of intravenous immunoglobulins. Steroids may be useful in the treatment of neutropaenia and of severe autoimmune manifestations.