Abstract Background: The course of chronic spontaneous urticaria (CSU) can be influenced by infections, depression, and stress. Objectives: Our aim was to investigate the impact of the COVID-19 pandemic on the course of refractory CSU together with patient adherence to omalizumab and treatment adjustments. Methods: Urticaria Activity Score (UAS7) was used to assess disease activity. Fear of COVID-19 Scale (FC-19s), and Depression Anxiety Stress Scale (DASS-21s) were performed to assess mental health status. All scales were performed during the Quarantine Period (QP) and Return to the Normal Period (RTNP). UAS7 Before Pandemic (BP) was recorded from the patients medical records. Results: The authors evaluated 104 omalizumab-receiving CSU patients. UAS7 scores during QP were significantly higher than those in RTNP and BP (p < 0.01). DASS-21 and FC-19 scores were significantly higher during QP compared to RTNP (p < 0.01). Nineteen (18.2%) patients ceased omalizumab, 9 patients prolonged the intervals between subsequent doses during the pandemic. UAS7 scores in QP were significantly higher in patients who ceased omalizumab than in those who continued (p < 0.001). Among patients who continued omalizumab, 22.4% had an increase in urticaria activity and higher FC-19 scores in comparison with those with stable disease activity (p = 0.008). Study limitations: The small sample size of patients with prolonged intervals of omalizumab and the lack of mental health evaluation with the same tools prior to the study. Conclusions: Fear induced by COVID-19 can determine an increase in disease activity. Therefore, patients on omalizumab should continue their treatment and prolonged interval without omalizumab can be considered in patients with good urticaria control.