Background: A previous study, using administrative data, reported an incidence of perioperative anaphylaxis (POA) of 1:6537 procedures in the United States. Objective: We sought to determine the incidence of POA in a prospective US cohort. Methods: Adult participants undergoing a procedure at a single tertiary care center were studied prospectively between April 2018 and January 2022. Subinvestigators recorded vital signs and skin checks preoperatively, 15 minutes into induction, and hourly thereafter until 1 hour into the postoperative period. If participants developed an adverse reaction, additional variables were documented: causal agent(s) exposure, type of nonallergic adverse reaction, Sixth National Audit Project severity score, evidence of mast cell activation by serum acute and baseline tryptase pairing, Allergy consult, and causal agent identification. Results: Among 939 procedures (mean age, 59.25 ± 14.78 years; 58% females; 87% White), there were 12 (1.3%) cases with an identified adverse reaction. Nine cases were classified as nonhypersensitivity adverse reactions (1%) and 3 as possible hypersensitivity reactions (0.3%); 1 case was classified as suspected perioperative hypersensitivity and 2 as POA (0.2%). Both POA cases were males, had previous procedures, had evidence of mast cell activation, had a Sixth National Audit Project score of 3, and were referred to Allergy for further evaluation. There were 9 participants who developed a nonhypersensitivity adverse reaction: relative overdose of anesthetic (n = 6), transient rash (n = 2), and isolated bronchospasm (n = 1). All transient rashes were observed during undraping protocol. Conclusions: In our prospective study, the incidence of POA is 1:470 procedures. Our study suggests that the incidence of POA may be higher than previously reported.