Objective To report a case of acute respiratory distress syndrome (ARDS) following first exposure to aprotinin. Case Summary A 24-year-old previously healthy white man was treated with aprotinin infusion because of bleeding following tonsillectomy. The patient had never been treated with aprotinin before, including local application of different hemostatics containing the aprotinin component. Two hours later, hypotension and severe ARDS developed. A full recovery was noted after discontinuation of the drug and prolonged ventilatory support. Discussion To our knowledge, this is the first reported case of ARDS following first administration of aprotinin, although serious adverse effects at first exposure have been reported. We propose two possible mechanisms for this adverse reaction: a nonallergic or anaphylactoid reaction with direct degranulation of mast cells and basophils by aprotinin, and microthrombosis of the small pulmonary arterioles precipitated by aprotinin. Conclusions Most clinicians consider aprotinin to be a safe drug, especially if it has not been administered before. Reexposure carries a high risk of allergic reactions because of possible sensitization. Nonimmunologic, toxic, or idiosyncratic adverse reactions can be expected at first exposure to any drug, as well as to aprotinin.