BACKGROUND: The impact of chronic spontaneous urticaria (CSU) on health-related quality of life (HRQoL) is widely held to be mainly influenced by disease activity and comorbidities. OBJECTIVE: To assess the correlation between disease activity and HRQoL impairment by using validated disease-specific instruments. METHODS: The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) was translated into Greek and subsequently applied to 110 CSU patients along with the Dermatology Life Quality Index and the Urticaria Activity Score. After the validity and reliability of the Greek CU-Q2oL had been determined, we assessed the relation between disease activity and HRQoL impairment by computing correlations as well as by performing multiple regression analysis. RESULTS: Exploratory factor analysis revealed a six-scale structure of the Greek CU-Q2oL that explained 67.9% of its total variance. The internal consistency was satisfactory with Cronbach's α >0.7. Disease activity was the only predictor of quality of life impairment, but it only moderately correlated with the CU-Q2oL total score (r = 0.40, p < 0.0001). CONCLUSION: Our results suggest that there are additional factors to disease activity that are responsible for the pronounced reduction of HRQoL in CSU, and this supports the recommendation to assess and monitor both disease activity and quality of life in CSU patients.