Hypogammaglobulinemia has been described as a secondary consequence of many disorders. It is also the seminal finding in many primary immune deficiencies. There are few studies examining the global etiologies of hypogammaglobulinemia. This study undertook a database discovery of all cases of laboratory-defined hypogammaglobulinemia identified in a large tertiary care pediatric hospital setting between August of 1990 until June of 2006. Eight thousand three hundred and four IgG levels were sent during that time frame. One thousand two hundred and ninety-five specimens from 680 individual patients exhibited hypogammaglobulinemia and these patients represent the study population. The majority of cases in whom an identifiable cause was found had pre-existing conditions and the IgG level was sent as part of a monitoring process. Of the 366 patients who had an IgG level obtained for diagnostic purposes, nearly half were found to have an immune deficiency. One hundred and seventy-two patients with an immune deficiency were identified. Seven percent of these had severe combined immune deficiency. Seventy-four percent of the immune deficient patients identified required active intervention with IVIG, bone marrow transplantation or other management (not including prophylactic antibiotics). Evaluating all patients with IgG levels less than half of the lower limit for age revealed 122 patients of whom 33% had a primary immune deficiency. This study provides a framework for considering causes of hypogammaglobulinemia. At the study institution, hypogammaglobulinemia was found most often as a secondary immune deficiency due to chemotherapy or from complex cardiac anomalies. The magnitude of the secondary hypogammaglobulinemia in a tertiary care setting requires public health consideration as these patients have an unknown risk of infection and an unknown risk of prolonged viral shedding; issues which could be important in epidemic settings.