Objective: The various off-label uses of intravenous immune globulin (IVIG), used for the treatment of immunodeficiency disorders, far exceeds its labeled indications. This study represents an effort to identify these uses. Methods: Clinical studies concerning the off-label uses of IVIG preparations were identified by searching the PUBMED (MEDLINE+) database from January 1, 1998 to January 1, 2006. The search was limited to clinical trials, meta-analyses, randomized controlled trials, and case reports in English. Results: A review of 138 clinical trial abstracts identified 10 trials examining 2 labeled uses (635 patients) and 128 trials examining 61 different off-label uses (6781 patients). The top off-label indications included multiple sclerosis, graft versus host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, and Guillan-Barre syndrome. The studies appear to support many of the acceptable off-label uses cited by various guideline groups. A total of 276 case reports were identified, with 268 reports representing 156 different off-label uses (362 patients). Patient outcomes from published abstracts were positive for 267 patients (74%). Seven meta-analyses were identified, evaluating recurrent miscarriage, in vitro fertilization failure, infection in preterm infants, multiple sclerosis, immune thrombocytopenic purpura, and pemphigoid. With the exception of recurrent miscarriage and infection in preterm infants, the off-label use of IVIG for these indications was found to have positive outcomes. Conclusion: Over 150 off-label uses were identified from reviewing clinical trials and case reports. An examination of IVIG guidelines by specialty society, payer, and other review organizations shows that the biomedical evidence supporting off-label uses is being interpreted in different ways. Healthcare institutions are strongly urged to approve and closely monitor specific uses of IVIG to reserve dwindling supplies for the “best evidence” uses. Clinicians should be aware of the limits of knowledge in many off-label uses and exercise restraint in prescribing for unproven indications.