In patients suffering from recurrent or chronic infections with encapsulated bacteria the humoral immune disorder of IgG subclass deficiencies is common (about 20%), yet insufficiently diagnosed because of the nonspecific symptomatology and the often unaffected levels of total immunoglobulin (Ig) isotypes. IgG subclass deficiency is correctly diagnosed by measurement of all four IgG subclasses. The IgG2-subclass deficiency is most frequent, often together with decreased IgG4-and/or IgA-levels. The IgG2-subclass deficiency is associated with a diminished immune response to (bacterial capsular) polysaccharide antigens. Although the anti-polysaccharide response is generally believed to be IgG2-restricted, a causal relationship between a decrease in IgG2 and disease is obscure. First, the precise meaning and contribution of IgG2 to the opsonization of encapsulated microorganisms is incompletely known. Second, several healthy individuals completely lack one or more isotype/subclasses due to (pseudo-) deletions of the genes, but still produce protective antibody titers in the residual Ig isotype or subclass. Third, young children mount protective titers of specific IgG1 antibodies against polysaccharides, whereas IgG2-subclass deficient children are prone to infection by encapsulated bacteria. In sum, decreases in IgG2 subclass levels may be merely epiphenomenal in a large group of patients who do not respond effectively to (bacterial) polysaccharides. New directions of investigation in order to obtain insight in the prevalence and pathogenesis of IgG subclass deficiencies are discussed.