Chronic spontaneous urticaria (CSU) is an important dermatological disease involving severe itchy urticaria lesions and/or angioedema. Urticaria and angioedema occur in the community at a rate of 25–30%. Many factors, such as inflammation, have been implicated in the etiology of CSU. Irisin is a newly identified adipocytokine shown by research to exhibit anti-inflammatory properties in addition to its many other effects. The aim of the study was to investigate, for the first time in the literature, the significance of serum irisin levels in patients with CSU. Seventy-eight individuals were evaluated. The study group included 44 patients diagnosed with CSU, and the control group consisted of 34 healthy individuals. Serum samples were collected, and serum irisin, Interleukin-2 (IL-2), Interleukin-3 (IL-3), Tumor Necrosis Factor-alpha (TNF-α), and Interferon-ɣ (IF-ɣ) levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. Irisin was studied for the first time in patients with CSU and exhibited a significantly higher level in the control group than in the patient group (p = 0.020). IL-2, IL-3, and IF-ɣ levels were higher in the CSU group than in the control group, although the results were not statistically significant. Only TNF-α results increased significantly. Correlation analysis was applied to determine the relationships between irisin and IF-ɣ and IL-3 levels. This revealed that the irisin parameter was significantly and positively correlated with IF-ɣ and IL-3 in patients with CSU (r = 0.518, p = 0.016 and r = 0.536, p = 0.022, respectively). This is the first report to evaluate irisin as an inflammatory biomarker in CSU. Irisin levels in patients with CSU were low, suggesting that irisin may pay a role in the pathogenesis of CSU and may be a marker showing the severity of the disease.