Although the National Kidney Foundation (NKF) has published clinical practice guidelines for the management of risk factors for cardiovascular disease, these guidelines have not been tested rigorously for their effectiveness. We conducted an observational study among patients with end-stage kidney disease to examine the prognostic impact of threshold levels recommended by the NKF for blood pressure, hemoglobin, calcium-phosphate product, parathyroid hormone, low-density lipoprotein, and glycosylated hemoglobin. The study population (N = 197) was assembled from a previously completed randomized trial examining arteriovenous graft thrombosis. Cox proportional hazard analysis was used to calculate hazard ratios for the association of levels outside guideline recommended targets and death, adjusting for age, comorbidity, race, and albumin. The proportion of patients outside guideline targets ranged from 33% to 81%, and the impact of levels outside guideline targets on mortality varied substantially. Elevated calcium-phosphate product and glycosylated hemoglobin had harmful effects, with adjusted hazard ratios of 1.58 (95% CI 1.00-2.50; p = 0.050) and 2.21 (95% CI 0.99-4.97; p = 0.054), respectively. Nontarget levels for blood pressure, hemoglobin, and parathyroid hormone had little effect, with adjusted hazard ratios of 1.15 (95% CI 0.74-1.78; p = 0.542), 1.04 (95% CI 0.65-1.68; p = 0.866), and 0.90 (95% CI 0.50-1.61; p = 0.722), respectively. Elevated low-density lipoprotein had a paradoxically beneficial effect, with an adjusted hazard ratio of 0.48 (95% CI 0.23-1.00; p = 0.049). These results suggest that the prognostic impact of current threshold levels recommended by select NKF guidelines on mortality is variable. Accordingly, the development and implementation of clinical practice guidelines should be accompanied by corresponding efforts to confirm their impact on patient outcomes. Such efforts are essential for the improvement of guidelines and to inform health policy optimally.