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Background: The pathophysiology of xerosis depends on extrinsic and intrinsic exposures. Residential hard water may constitute such an exposure. Objectives: To estimate the prevalence of xerosis and to compare water hardness exposure in blood donors with and without xerosis. Methods: In this retrospective cohort study in 2018–2019, blood donors with self-reported moderately or severely dry skin were compared to blood donors without dry skin. Blood donors with ichthyosis, lichen planus and psoriasis were excluded. Water hardness data was collected from the Geology Survey of Denmark and Greenland. Results: Overall, 4,748 of 30,721 (15.5%; 95% confidence interval 15.1–15.9%) blood donors had xerosis. After excluding blood donors with ichthyosis, lichen planus and psoriasis, 4,416 blood donors (2,559 females; median age 38.4 years [interquartile range 28.0–49.8]; 700 smokers) remained in this study. Water softer than 12–24 degrees Deutsche härte was associated with decreased probability of xerosis (odds ratio 0.83; 95% confidence interval 0.74–0.94) and water harder than 12–24 degrees Deutsche härte was associated with increased probability of xerosis (odds ratio 1.22; 95% confidence interval 1.03–1.45). The association between water hardness and xerosis remained significant after excluding blood donors with dermatitis. Conclusions: Water hardness is associated with xerosis independent of other dermatoses. [ABSTRACT FROM AUTHOR]