Background/Objectives: Human β-defensin 2 (HBD2) is a protein that plays an important role in activating the immune system by modulating spinal pathways and the inflammatory response. According to previous research, HBD2 was proven to be important in chronic spontaneous urticaria (CSU) (their values were significantly elevated in CSU patients, with a significant correlation between HBD2 levels and the percentage of peripheral basophils, suggesting that elevated HBD2 levels may be a potential marker of basophil and mast cell activation), which led us to additional research on the HBD2 molecule in isolated chronic angioedema. The aim of this research is to examine HBD2 values in the saliva and serum of patients with isolated angioedema, as a potential biomarker of the disease. Methods: This cross-sectional study involved a total of 102 participants, involving three groups: 33 patients with isolated chronic non-hereditary angioedema (AE) (defined as sudden onset of localized edema without chronic urticaria), 33 patients with angioedema associated with chronic urticaria (CU+AE), and 35 healthy participants (controls, CTRL). They provided a saliva sample to determine HBD2 levels using an ELISA (Enzyme-Linked Immunosorbent Assay). Subsequently, a peripheral blood sample (serum) was taken from the participants to determine HBD2 levels using the same ELISA. Results: Salivary HBD2 levels were significantly higher in those with CU+AE than in the CTRL (p = 0.019). While salivary HBD2 values differed between those with angioedema and CTRL, the serum HBD2 values did not. Also, no correlation between the levels of HBD2 in saliva and serum was found. Conclusions: Since we found that salivary HBD2 values were significantly higher in those with CU+AE than in CTRL, this points to a possible role of the HBD2 molecule in pathogenesis of AE (namely, that it induces degranulation in mast cells and vascular permeability, and has antimicrobial properties) Therefore, more research is needed to determine how reliable salivary HBD2 measurement is, as well as its significance.