Background: Uromodulin (UMOD), the most abundant protein found in the urine of healthy persons, is produced exclusively by the kidney and has emerged as a promising biomarker of tubule health. Methods: We evaluated associations of serum UMOD levels at baseline and percent change over time with subsequent risk of incident ESKD and mortality among African American Study of Kidney Disease and Hypertension trial participants. UMOD levels were measured from stored samples from the 0, 12, and 24- month visits using immunoassays. Covariates included baseline age, sex, systolic blood pressure, smoking, GFR, proteinuria, and randomized treatment groups. In secondary analysis, we evaluated whether randomized blood pressure goal or drug were associated with UMOD slopes. Results: Among 500 participants with baseline serum UMOD levels (mean age 54 years; 37% female), 161 ESKD events occurred over a median of 8.5 years. Each 2-fold higher baseline UMOD level was associated with a 27% lower risk of ESKD (HR: 0.73; 95% CI: 0.58, 0.92). For annual UMOD change, each 1 standard deviation (SD) higher change was associated with a 40% lower risk of ESKD (HR: 0.60; 95% CI: 0.50, 0.71). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply with intensive vs. standard BP goals (-2.13% per year), whereas ramipril vs. metoprolol was associated with greater increases (3.32% per year). Conclusions: Among African American adults with CKD and hypertension, higher UMOD levels at baseline and higher percent change in UMOD over time were associated with lower risk of subsequent ESKD.