Background Omalizumab is a third-line treatment for chronic spontaneous urticaria (CSU). However, the real-life data on the impact of omalizumab on CSU-related quality of life (QoL) remain scarce. Objectives To investigate the impact of omalizumab on QoL and its predictors in CSU. A retrospective cohort study was done. The response to therapy was evaluated using urticaria activity score over 7 days (UAS7) and urticaria control test (UCT); the impairment in QoL was assessed using dermatology life quality index (DLQI) and chronic urticaria quality of life questionnaire (CU-Q2oL). Results Forty-two patients were included. All scores improved from baseline to first month and remained stable at the third month of treatment (p < .001). The gender, age, and angioedema had no significant effect on QoL, but the complete responders (UAS7:0-1) had better improvement rates in all scores compared to others. The baseline UAS7, DLQI, and CU-Q2oL scores were lower at the baseline in complete responders (p = .0001). Conclusions A rapid and continual improvement in QoL was obtained with omalizumab treatment. A better UAS7, UCT, DLQI, and CU-Q2oL score at the baseline might be a predictor of a better response to omalizumab and more improvement in QoL.