Human IgG responses to carbohydrate antigens, such as those found on many infectious bacteria, are primarily restricted to the IgG2 subclass. This phenomenon, known as isotype restriction, has led us and others to examine the prevalence of IgG2 deficiency among infection-prone individuals. IgG2 deficiency (below 3 SD of the age group mean) is fairly common among patients suffering from chronic bacterial infections and suggests the utility of IgG subclass measurements in evaluating such patients. However, we also describe exceptions to isotype restriction in human responses to carbohydrate antigens. Furthermore, we describe individuals who, while responding very poorly to carbohydrate antigens, have normal IgG2 levels for their age group. These findings indicate the complexity of IgG subclass regulation and suggest that evaluation of infection-prone individuals should include measurements of both IgG subclasses and antibodies to carbohydrate antigens such as phosphocholine.