The purpose of this report is to describe an unusual presentation of anaphylaxis after first-time rattlesnake envenomation. A patient on a medical toxicology inpatient service is presented who had signs of anaphylaxis, including airway compromise, after first-time rattlesnake envenomation. An epinephrine drip and oral intubation were initiated. This case is unusual in that dermal and gastrointestinal exposure may have been the primary sensitization process that preceded a severe anaphylactic reaction after envenomation. The patient's recovery was prolonged. In conclusion, rattlesnake envenomation may result in rapidly progressive airway compromise, possibly caused by anaphylaxis in patients with previous dermal or gastrointestinal exposure to snake proteins.