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Aspirin and other nonsteroidal anti-inflammatory drugs that inhibit COX-1 induce unique nonallergic reactions, consisting of attacks of rhinitis and asthma. These hypersensitivity reactions occur in a subset of asthmatic subjects, thus identifying them as having this exclusive clinical presentation. We refer to these patients as having aspirin-exacerbated respiratory disease, a disease process that produces devastating eosinophilic inflammation of both the upper and lower respiratory tracts. This review focuses on a description of patients with aspirin-exacerbated respiratory disease, methods available to diagnose their condition, the unique ability of all nonsteroidal anti-inflammatory drugs that inhibit COX-1 to cross-react with aspirin, an update on pathogenesis, and current thoughts about treatment.