We hypothesize that delayed natriuresis during mental stress increases the risk of hypertension and other diseases. Our preclinical studies demonstrate an important role for renal endothelin-1 (ET-1) in regulating sodium excretion. Thus, we predict ET-1 may be linked to the delayed stress response in at-risk individuals. We hypothesize that reduced renal ET-1 accounts for derangements in sodium handling under stress, a link never explored in a large human cohort. We determined urinary ET-1 excretion in three observational studies of changes in sodium excretion during mental stress, in which 776 healthy youth (15–19 years) enrolled in a 5-hour protocol (2 hours of rest before and after 1 hour of mental stress). In all studies, 60-minute urine samples were obtained throughout the protocol. Subjects were grouped as retainers (reduced sodium excretion during stress relative to baseline) or excreters (increased sodium excretion during stress relative to baseline). In excreters, ET-1 excretion was significantly increased from baseline to stress (+0.02 pg/min; P <.001). In contrast, ET-1 excretion was significantly higher (P =.028) in retainers than excreters at baseline but significantly reduced in retainers under stress (−0.02 pg/min; P <.001). ET-1 excretion declined further in retainers during recovery but returned to prestress levels in excreters. Albumin excretion and albumin-to-creatinine ratio were significantly higher in retainers (P =.022, P <.001, respectively). Thus, loss of ET-1–dependent natriuresis may account for sodium retention during stress and may predispose retainers to renal diseases such as hypertension and kidney disease.