Background: Omalizumab resistance (OmR) in chronic spontaneous urticaria (CSU) remains poorly understood. Objective: To identify clinical and laboratory attributes of patients that may be predictive of OmR in CSU. Methods: We conducted a retrospective observational study by using an electronic patient record data base of patients with severe CSU refractory to a fourfold H1-antihistamine dose, treated with omalizumab 300 mg every 4 weeks for at least 24 weeks. Complete response (CR) was defined as the reduction of baseline urticaria activity score by ≥ 90%, partial response (PR) by ≥ 30% to <90%, and OmR by <30% at 24 weeks. The patient characteristics of the CR, PR, and OmR groups were compared. Results: Sixty-three patients (58.9%) had a complete remission at 24 weeks of omalizumab therapy, and 16 patients (14.9%) had OmR. The patients who were OmR were characterized by a higher rate of arterial hypertension 7 (43.8%), higher mean ± standard deviation (SD) high-sensitivity C-reactive protein (hs-CRP) level (10.3 ± 8.2 mg/L), mean ± SD white blood cell (WBC) count (9.1 ± 2.8 × 10³ cells/mL), and higher mean ± SD C3 level (164.3 ± 45.4 mg/dL) at baseline than the patients with CR (arterial hypertension, 9 [13.1%], p = 0.009; mean ± SD hs-CRP, 3.4 ± 10.1, p = 0.014; mean ± SD WBC count, 6.5 ± 3.8 × 10³ cells/mL, p = 0.012; and mean ± SD C3 level, 121.8 ± 42.1 m/dL, p < 0.001). In multivariable analysis adjusted for age, sex, and body mass index, OmR was associated with an hs-CRP level of >3.0 mg/L (odds ratio 1.94 [95% confidence interval, 1.28-3.15], p = 0.009) and with C3 > 160 mg/dL (odds ratio 1.54 [95% confidence interval, 1.05-2.36], p = .017). Conclusion: Obesity, arterial hypertension, high plasma C3 level, and high-CRP level were associated with OmR in severe CSU.