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RATIONALE: Hereditary angioedema (HAE) is an autosomal dominant disease caused by the lack of or a dysfunctional C1-inhibitor protein, affecting the skin, mucosal tissues of the upper respiratory tract and gastrointestinal (GI)tract. Trauma, infections, stress, and drugs such as estrogen-containing medications, and angiotensin-converting enzyme inhibitors are known triggers. Heroin use precipitating attacks has never been reported. Herein, we report the cases of identical twins with angioedema leading to respiratory failure after heroin use. METHODS: Single-center retrospective observational case series RESULTS: 55-year-old female twins with confirmed HAE since childhood presented one week apart with severe angioedema attack both precipitated immediately following abuse of heroin. Urine toxicology screen was positive for heroin. The first sister presented to the emergency department (ED) with angioedema flare of her upper airway. Her course was uncomplicated as she already had tracheostomy placement from previous attack and her flare rapidly resolved after C1 esterase replacement therapy. One week later, her twin sister presented to the ED with similar symptoms immediately after heroin use and she required mechanical ventilatory support. Her flare also resolved post administration of C1 esterase. Both were released from the hospital improved. CONCLUSIONS: These 2 patients are the first reported cases of angioedema attacks resulting from heroin abuse and illustrate management challenges. HAE is known for painful flares involving the GI tract, which can often predispose patients to narcotic dependence for pain relief. In addition to medications, long-term management of HAE is avoiding the triggers. More research needs to be done regarding illicit drug abuse HAE attacks.