Existing grading systems for acute systemic hypersensitivity reactions vary considerably, have a number of deficiencies, and lack a consistent definition of anaphylaxis. The aims of this study were to develop a simple grading system and definition of anaphylaxis and to identify predictors of reaction severity. Case records from 1149 systemic hypersensitivity reactions presenting to an emergency department were analyzed retrospectively. Logistic regression analyses of the associations between individual reaction features and hypotension and hypoxia were used to construct a grading system. Epinephrine use, etiology, age, sex, comorbidities, and concurrent medications were then assessed for their association with reaction grade. Confusion, collapse, unconsciousness, and incontinence were strongly associated with hypotension and hypoxia and were used to define severe reactions. Diaphoresis, vomiting, presyncope, dyspnea, stridor, wheeze, chest/throat tightness, nausea, vomiting, and abdominal pain had weaker, albeit significant, associations and were used to define moderate reactions. Reactions limited to the skin (urticaria, erythema, and angioedema) were defined as mild. These grades correlated well with epinephrine usage. Older age, insect venom, and iatrogenic causes were independent predictors of severity. Preexisting lung disease was associated with an increased risk of hypoxia. This simple grading system has potential value for defining reaction severity in clinical practice and research settings. The moderate and severe grades provide a workable definition of anaphylaxis. Age, reaction precipitant, and preexisting lung disease appear to be the major determinants of reaction severity.