Background: Urine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes. Methods: Using a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression. Results: The median value of uUMOD was 25.8 μg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment. Conclusion: Higher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.