A 66-year-old man with clinically localized prostate cancer had elected brachytherapy as the primary management of his disease. During induction of neoadjuvant androgen deprivation for purposes of cytoreduction, the patient experienced anaphylaxis immediately after his first injection of a leuprolide acetate depot. He required emergent intubation and extended hospitalization. Anaphylactic reactions to leuprolide acetate depots have been described as exceedingly rare. To our knowledge, we report the first case of an anaphylactic reaction to a leuprolide acetate depot injection in an American man undergoing treatment for prostate cancer.