Background: Mast cell–mediated angioedema (MC-AE) is considered a form of chronic spontaneous urticaria (CSU). Objective: To investigate the clinical and laboratory features that distinguish MC-AE from antihistamine-responsive CSU (CSU), and antihistamine-resistant CSU (R-CSU) with and without concomitant AE. Methods: A retrospective observational study using the electronic patient record data base of patients with MC-AE, CSU, R-CSU, and sex- and age-matched control group (control), with a case-control ratio of 1:2. Results: A total of 986 subjects in the CSU group, 148 in the R-CSU group, 64 in the MC-AE group, and 1198 in the control group were compared. The R-CSU group without AE was characterized by lower total IgE levels (118.5 6 84.7 IU/mL) and higher High sensitivity-C reactive protein (hs-CRP) levels (138.9 6 94.2 IU/mL, p = 0.027; and 7.4 6 6.9 mg/L versus 5.1 6 6.8 mg/L, p = 0.001) than the CSU without AE group. The R-CSU group with AE was characterized by lower total IgE levels (112.1 6 81.3 IU/mL) than the CSU group with AE (141.7 6 89.5 IU/mL; p < 0.001), higher hs-CRP levels (7.1 6 6.1 mg/L versus 4.7 6 5.9 mg/L; p < 0.001). There were fewer female subjects in the MC-AE group (31 [48.4%]) than in the CSU with AE and in the R-CSU with AE 223 (67.8%) and 18 (66.7%), respectively; p = 0.012). MC-AE group was characterized by less eyelid/perioral/facial involvement and more limb involvement than in the CSU with AE and R-CSU with AE groups (p < 0.001). Conclusion: Low IgE in MC-AE and higher IgE in CSU may signify two distinct types of immune dysregulation. Due to clinical and laboratory differences between MC-AE and CSU, we suggest questioning the assumption that MC-AE is a form of CSU.