Leukoaraiosis refers to lesions with high signal intensity on magnetic resonance imaging (MRI) in periventricular and subcortical white matter that results from chronic microvascular ischemic brain damage. Increasing evidence suggests that serum CA 19-9 is associated with non-malignant conditions including type 2 diabetes, dyslipidemia, and metabolic syndrome, which are closely related to microangiopathy. Thus, we hypothesized that serum CA 19-9 levels would be associated with cerebrovascular microangiopathy measured by leukoaraiosis among middle-aged and older adults. This cross-sectional study included 1833 Korean adults aged ≥45 years who participated in a health examination program between 2010 and 2011. Serum CA 19-9 levels were quantified by chemiluminescence immunoassay and categorized as quartiles: Q1: ≤4.5, Q2: 4.6-7.5, Q2: 7.6-12.2, and Q4: ≥12.3 ng/mL. Odds ratios (ORs) and 95% confidence intervals (CIs) for leukoaraiosis based on brain MRI scans were calculated across serum CA19-9 quartiles using multiple logistic regression analysis. The overall prevalence of leukoaraiosis was 4.6% and increased with serum CA 19-9 quartiles. Compared to the lowest quartile, the OR (95% CI) of the highest CA 19-9 quartile for leukoaraiosis was 2.20 (1.10-4.42) after adjusting for age, sex, BMI, regular exercise, hypertension, type 2 diabetes, dyslipidemia, smoking status, and alcohol drinking. Serum CA 19-9 levels were positively and independently associated with leukoaraiosis. Our findings indicate that serum CA 19-9 level might be a useful additional measure for assessing cerebrovascular microangiopathy in clinical settings. Copyright © 2019 Elsevier B.V. All rights reserved.