OBJECTIVE: Aortic surgeries requiring hypothermic circulatory arrest evoke systemic inflammatory responses that often manifest as vasoplegia and hypotension. Because mast cells can rapidly release vasoactive and proinflammatory effectors, we investigated their role in intraoperative hypotension. METHODS: We studied 31 patients undergoing proximal aortic repair with hypothermic circulatory arrest between June 2013 and April 2015 at Duke University Medical Center. Plasma samples were obtained at different intraoperative time points to quantify chymase, interleukin-6, interleukin-8, tumor necrosis factor alpha, and white blood cell CD11b expression. Hypotension was defined as the area (minutes × millimeters mercury) below a mean arterial pressure of 55 mm Hg. Biomarker responses and their association with intraoperative hypotension were analyzed by 2-sample t test and Wilcoxon rank sum test. Multivariable logistic regression analysis was used to examine the association between clinical variables and elevated chymase levels. RESULTS: Mast cell-specific chymase increased from a median 0.97 pg/mg (interquartile range [IQR], 0.01-1.84 pg/mg) plasma protein at baseline to 5.74 pg/mg (IQR, 2.91-9.48 pg/mg) plasma protein after instituting cardiopulmonary bypass, 6.16 pg/mg (IQR, 3.60-9.41 pg/mg) plasma protein after completing circulatory arrest, and 7.64 pg/mg (IQR, 4.63-12.71 pg/mg) plasma protein after weaning from cardiopulmonary bypass (each P value < .0001 vs baseline). Chymase was the only biomarker associated with hypotension during (P = .0255) and after (P = .0221) cardiopulmonary bypass. Increased temperatures at circulatory arrest and low presurgical hemoglobin levels were independent predictors of increased chymase responses. CONCLUSIONS: Mast cell activation occurs in cardiac surgery requiring cardiopulmonary bypass and hypothermic circulatory arrest and is associated with intraoperative hypotension.