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The prevalence of perioperative anaphylaxis is 1 in 1250-20,000 anesthetics. Inhalational anesthesia is considered safe in patients with multiple drug allergies, as there have been no reports of anaphylaxis to volatile inhalational agents. Anesthetic management of six patients with documented allergy to all commonly used anesthetic drugs who underwent major surgeries under general anesthesia is described as a case series. The plan of anesthesia in these patients was an anesthetic gas-based general anesthesia without using muscle relaxants but with the use of intravenous fentanyl if patient was not allergic to it. Sevoflurane 8% in oxygen was used for induction. Following cessation of breathing and on attaining an end-tidal concentration of >4% sevoflurane, direct laryngoscopy and intubation were performed. Anesthesia was maintained with sevoflurane in nitrous oxide and oxygen mixture maintaining a lower end-tidal carbon dioxide. Hypotension and/or bradycardia were managed with intermittent intravenous boluses of adrenaline 20 μg. At the end of surgery, all anesthetic gases were cutoff, and patients were extubated when awake. No muscle relaxant was used in any of the cases. Two patients received fentanyl before induction, whereas others were given oral paracetamol 2 h before induction. Postoperative analgesia was provided with oral paracetamol which was given 2-4 h after surgery. Intraoperative period was uneventful for these patients. In patients with multiple drug allergies, inhalational agent-based general anesthesia can be considered as a safe alternative to regular anesthetic practice involving polypharmacy, with a reduced risk of perioperative adverse events.