Background: The impact of hand eczema (HE) on Health-Related Quality of Life (HRQoL) has only been sparsely studied in a general population setting, and never by use of the disease specific Quality Of Life in Hand eczema Questionnaire (QOLHEQ). Objectives: To examine the HRQoL of unselected individuals with HE using the QOLHEQ. Further, to provide prevalence estimates of severe and chronic HE (CHE), and to contrast overall health related outcomes between individuals with and without HE. Methods: In this nationwide, cross-sectional study a questionnaire covering questions on HE related outcomes, and overall health was sent to a random sample of 100 000 Danish adults via a secure digital mailbox, linked to their unique civil registration numbers. Data on demographic characteristics were retrieved from the civil registration system. Individuals reporting HE, further answered the QOLHEQ and other disease specific questions. Results: The response rate was 42.7% (n = 42 691). Total estimates of lifetime, 1-year and point prevalences of HE were 24.4%, 13.3% and 5.8%. Of individuals reporting a 1-year prevalence, 35.1% reported moderate–severe disease and 82.6% CHE. Individuals with HE were more likely to report less good or poor overall health, and sick leave (any reason), compared to those without. In the 2176 (92.5%) with current HE who completed the QOLHEQ, median QOLHEQ scores corresponded to a moderate impairment of the symptoms and treatment and prevention domains and a slight impairment overall and for the emotions and functioning domains. Factors that were strongly associated with moderate to severe HRQoL impairment included severe, chronic and occupational HE as well as female sex. Conclusions: HE is highly prevalent, bears a considerable burden on society and significantly affects the lives of impacted individuals. Our findings indicate a necessity for targeted prevention aimed at high-risk groups, and support and treatment for those most affected.