Immunodeficiency with hyper-IgM was described by Israel-Asselain et al. in 1960 [1] and Rosen et al. in 1962 [2]. It is characterized by recurrent infections, very low or undetectable levels of IgG and IgA, normal to increased serum IgM [3], and is rare. Both primary and acquired forms of the disease have been reported: hyper-IgM syndrome may be secondary to congenital rubella [4], tumours [5], or use of anti-epileptic drugs [6]. Among primary hyper-IgM syndrome, genetic heterogeneity is supported by the existence of X-linked [7], autosomal recessive [8], and possibly autosomal dominant [9] variants. This review focuses on the X-linked variant of hyper-IgM syndrome (XHIM) that results from defects of the gene for CD40 ligand (CD40L, now renamed CD154)[10±14]. Molecular characterization and the development of specific disease Registries in Europe [15, 16] and in the USA have helped with the identification of the clinical features of XHIM. Most XHIM patients present in infancy with upper and lower respiratory tract infections. In contrast to other forms of hypogammaglobulinaemia, XHIM patients are uniquely susceptible to interstitial pneumonia caused by Pneumocystis carinii (PC). This infection affects as many as 20±40% of the patients and often marks clinical onset ([16±18], Fig. 1). Protracted diarrhoea is also common, and may be severe enough to require total parenteral nutrition in order to avoid malnutrition [19]. Cryptosporidium parvum (CP) infection has been found in about 30% of the cases with chronic diarrhoea [16], and is also involved in sclerosing cholangitis, another severe manifestation of XHIM [20, 21]. Liver disease as a whole is common in XHIM, and its frequency appears to increase with age [21]; in addition to sclerosing cholangitis, XHIM patients may develop chronic hepatitis (due to hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV)), possibly progressing to cirrhosis. Furthermore, an unusual susceptibility to liver and biliary tract tumours (in addition to lymphomas) has been reported in XHIM [21].