Subcutaneous immunotherapy (IT) with aeroallergen extracts is venerable treatment modality. The major risk associated with IT with commercial aeroallergen extracts is the uncommon occurrence of severe near-fatal or fatal anaphylaxis after injections. The objectives of this article are to review the reported incidences of severe anaphylaxis (near-fatal reactions and fatal reactions), define factors contributing to these events, and identify preventive measures that are likely to reduce or eliminate future fatal and near-fatal anaphylactic events. As with any treatment, anticipated benefits attributed to IT must be weighed against its potential risks.