BACKGROUND: Anaphylaxis during anaesthesia is a serious complication for patients and anaesthetists. METHODS: The Sixth National Audit Project (NAP6) of the Royal College of Anaesthetists examined the incidence, predisposing factors, management, and impact of life-threatening perioperative anaphylaxis in the UK. NAP6 included: a national survey of anaesthetists' experiences and perceptions; a national survey of allergy clinics; a registry collecting detailed reports of all Grade 3-5 perioperative anaphylaxis cases for 1 yr; and a national survey of anaesthetic workload and perioperative allergen exposure. NHS and independent sector (IS) hospitals were approached to participate. Cases were reviewed by a multi-disciplinary expert panel (anaesthetists, intensivists, allergists, immunologists, patient representatives, and stakeholders) using a structured process designed to minimise bias. Clinical management and investigation were compared with published guidelines. This paper describes detailed study methods and reports on project engagement by NHS and IS hospitals. The methodology includes a new classification of perioperative anaphylaxis and a new structured method for classifying suspected anaphylactic events including the degree of certainty with which a causal trigger agent can be attributed. RESULTS: NHS engagement was complete (100% of hospitals). Independent sector engagement was limited (13% of approached hospitals). We received >500 reports of Grade 3-5 perioperative anaphylaxis, with 266 suitable for analysis. We identified 199 definite or probable culprit agents in 192 cases. CONCLUSIONS: The methods of NAP6 were robust in identifying causative agents of anaphylaxis, and support the accompanying analytical papers.