Magnesium deficiency is common in patients with chronic kidney diseases (CKD) due to restricted magnesium intake and impaired magnesium reabsorption. Based on pathophysiological risk factors influencing kidney magnesium reabsorption, a magnesium depletion score (MDS) was developed. Using MDS as a novel indicator for assessing body magnesium status, we hypothesized that it was associated with clinical prognosis.We conducted a prospective population-based cohort study using data from the National Health and Nutrition Examination Survey 1999-2014 to explore the impact of MDS on the clinical outcomes of CKD patients. Propensity score-matched analyses were conducted to increase comparability. The primary outcome was all-cause mortality, and the secondary outcomes were cardiovascular-cause and cancer-cause mortality.After propensity score matching, 3294 CKD patients were divided into 2 groups: MDS ≤ 2 (N = 1647), and MDS > 2 (N = 1647). During a median follow-up of 75 months, Kaplan-Meier analyses showed that MDS > 2 was associated with worse 5- and 10-year overall survival (78.5% vs 73.4%; 53.1% vs 43.1%, P < 0.001). After adjusting for confounding variables, MDS was found to be an independent risk factor for all-cause mortality (HR:1.34, 95% CI 1.20-1.50, P < 0.001). MDS > 2 was also associated with higher cardiovascular-cause mortality (16.2% VS 11.6%, P = 0.005). Multivariate competing risk analysis revealed that MDS > 2 was an independent risk factor (HR: 1.33, 95% CI 1.06-1.66, P = 0.012). Subgroup analyses reported that MDS > 2 increased all-cause mortality and cardiovascular-cause mortality only in patients with inadequate magnesium intake (P < 0.001, P < 0.001) but not in those with adequate intake (P = 0.068, P = 0.920).A magnesium depletion score > 2 was independently associated with higher long-term cardiovascular-cause and all-cause mortality in CKD patients.© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.