Hydration status significantly affects the clinical outcome of acute ischemic stroke (AIS) patients. Blood urea nitrogen-to-creatinine ratio (BUN/Cr) is a biomarker of hydration status. However, it is not known whether there is a relationship between BUN/Cr and three-month outcome as assessed by the modified Rankin Scale (mRS) score in AIS patients.AIS patients admitted to West China Hospital from 2012 to 2016 were prospectively and consecutively enrolled and baseline data were collected. Poor clinical outcome was defined as three-month mRS > 2. Univariate and multivariate logistic regression analyses were performed to determine the relationship between BUN/Cr and three-month outcome. Confounding factors were identified by univariate analysis. Stratified logistic regression analysis was performed to identify effect modifiers.A total of 1738 patients were included in the study. BUN/Cr showed a positive correlation with the three-month outcome (OR 1.02, 95% CI 1.00-1.03, p=0.04). However, after adjusting for potential confounders, the correlation was no longer significant (p=0.95). An interaction between BUN/Cr and high-density lipoprotein (HDL) was discovered (p=0.03), with a significant correlation between BUN/Cr and three-month outcome in patients with higher HDL (OR 1.03, 95% CI 1.00-1.07, p=0.04).Elevated BUN/Cr is associated with poor three-month outcome in AIS patients with high HDL levels.