Low levels of single or multiple serum immunoglobulin G (IgG) subclasses is a common finding among patients with increased susceptibility to infections. In this investigation we summarize data from studies of 503 subclass-deficient individuals. Low IgG2 levels was the most common deficiency among children, and boys were more often deficient than girls. From the age of 16, females dominated, and the most frequent finding was low IgG3 levels. In vitro T or B lymphocyte dysfunction was demonstrated in 75% of the individuals, suggesting that low subclass levels may be indicators of an underlying defect at the B cell or possibly T cell level. Vaccinations and mucosal biopsies were performed to evaluate which patients may be helped by immunoglobulin substitution therapy.