Acute allergic reactions range from mild conditions of local tissue swelling and pruritus to severe multisystem syndromes including asthma, urticaria and/or angioedema, gastrointestinal distress, and vascular collapse. Such reactions share a common pathophysiology characterized by vasodilation and postcapillary permeability, resulting in increased extravasation of fluid within minutes after exposure to an eliciting substance. Smooth muscle contraction of the respiratory or gastrointestinal tracts may also be involved. Most of these changes can be explained by the release of chemical mediators from circulating basophilic leukocytes and tissue mast cells. Human basophils and mast cells can be activated to release chemical mediators by several known pathways: crosslinking by allergens of specific immunoglobulin E antibodies attached to basophils and mast cells; anaphylatoxin formation following immune complex activation of the classical complement pathway; anaphylatoxin formed from direct activation of the alternative complement pathway by negatively charged surfaces; non-complement-, non-antibody-mediated direct histamine release; and idiosyncratic mechanisms involving physical exercise, psychological stress, or aspirin intolerance. Any or all of these mechanisms could be operative in patients experiencing acute allergic reactions at the commencement of hemodialysis.