Irukandji syndrome (IS) is an extremely painful condition that causes a significant catecholamine surge and sympathetic autonomic response related to the envenomation from certain types of jellyfish. Current management involves intravenous fluids, magnesium sulphate and large doses of opioids for symptom control. Clonidine, a centrally acting alpha-2 agonist, is often used as an analgesic adjunct to reduce opioid requirements in acute pain. The present study explores the safety and efficacy of clonidine in reducing opioid requirements in IS. All patients diagnosed with IS at Cairns Hospital between 1 March 2016 and 30 April 2020, and participants from the Magnesium in Irukandji Study Trial, were included in this retrospective study (n= 114). Cases were separated into two groups depending on whether or not they received clonidine, and subsequently analysed according to pre- and post-intervention opioid requirements, clonidine dose administered and adverse effects. Notably, 39 patients with IS received ≥1 mcg/kg clonidine and the remaining 75 did not. There was no difference in oral morphine equivalent daily dose (oMEDD) between groups before clonidine administration; however, there was a significant reduction in oMEDD required after patients received clonidine (26.1 mg; 95% CI 4.6-47.7) compared with those who did not (66.6 mg; 95% CI 56.9-86.1) (F= 8.722, df= 1 × 224, P= 0.003). One episode of hypotension occurred following the intervention. Patients with IS who received clonidine required significantly lower opioid requirements than those who did not receive clonidine. Clonidine was safe to administer and should be considered early when treating IS. The optimal clonidine dose remains unclear and requires prospective studies to validate our findings.