Background: Fatigue is a common and disabling symptom in chronic inflammatory diseases. To the best of our knowledge, there are no studies evaluating fatigue thoroughly in patients with chronic spontaneous urticaria (CSU). Objectives: To evaluate fatigue and its drivers in patients with CSU, and to compare patients with healthy controls in terms of fatigue. Methods: One hundred and three patients with CSU and 35 age- and gender-matched healthy control subjects were evaluated for fatigue with the Fatigue Severity Scale (FSS) and visual analog scale-fatigue. Patients were also assessed for their duration, activity, and control of disease, as well as anxiety, depression, and quality of life (QoL). Results: There were no significant associations between disease activity, disease control scores, and FSS (P >.05). Although there were no significant differences in terms of antinuclear antibody positivity and IgE levels between fatigued and nonfatigued patients with CSU, C-reactive protein levels were higher in fatigued patients (P =.009). A significant correlation was noted between total FSS score and both Chronic Urticaria-QoL (r = 0.246, P =.013) and Dermatology Life Quality Index (r = 0.302, P =.002) in patients with CSU. In regression analyses, female gender and the presence of disturbed sleep were found to be significant predictors of fatigue in patients with CSU (P =.008; odds ratio [OR]: 9.02, and P =.001; OR: 8.35). Conclusion: Fatigue is a common and important symptom in patients with CSU and adversely affects QoL. While evaluating patients with CSU, it is important to assess fatigue, especially in female gender patients and in those having sleep disturbance.