Anaphylaxis in the operating room although infrequent can be potentially fatal. The diagnosis of perioperative anaphylaxis is complex due to a multitude of factors. Firstly, patients under anesthesia cannot verbalize their complaints, the anesthetic agents themselves can alter vital parameters (e.g. heart rate and blood pressure) and cutaneous signs in a completely draped patient may be missed. Secondly, the differential diagnosis of intraoperative anaphylaxis is wide. Conditions such as asthma exacerbation, arrhythmia, hemorrhage, angioedema, mastocytosis, acute myocardial infarction, drug overdose, pericardial tamponade, pulmonary edema, pulmonary embolus, sepsis, tension pneumothorax, vasovagal reaction, venous air embolism, laryngospasm, blood transfusion reaction and malignant hyperthermia need to be considered. Thirdly, the diagnostic workup is challenging due to the multiple medications administered and other exposures encountered such as latex and chlorhexidene. However, through a timely allergy consultation and a systematic approach, identification of the culprit agent and safe alternatives can be established to prevent future occurrences as illustrated in the case below.