Background: While experimental models show that leptin and adiponectin have inverse effects on the cardiovascular system, it has been suggested that the leptin-to-adiponectin (L/A) ratio may be an important predictor of cardiovascular disease and death. Higher circulating leptin and adiponectin levels are observed in uremia due to decreased renal degradation and/or clearance and increased production. We sought to examine the association between the L/A ratio and mortality in a prospective hemodialysis cohort. Methods: Among a prospective cohort of 448 hemodialysis patients from the NIH “Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease (CKD) (MADRAD) study who underwent leptin and adiponectin measurements, we examined characteristics associated with high leptin and adiponectin (defined as the highest tertile) using logistic regression. We then examined the association of L/A ratio levels (categorized as tertiles) with all-cause mortality using Cox regression. Results: Multivariable logistic regression analyses showed female sex, diabetes, presence of an arteriovenous fistula/graft, and lower serum albumin, IL-6, and adiponectin were associated with high leptin, whereas female sex, longer vintage, Black race, higher IL-6, and lower leptin were associated with high adiponectin. When examining L/A ratios, the highest tertile was associated with lower mortality in case-mix Cox models (ref: lowest tertile): HR (95% CI) 0.14 (0.06–0.35). These associations were robust in analyses that additionally adjusted for laboratory covariates: (HR 95% CI) 0.18 (0.07–0.46). Conclusions: In a prospective cohort of hemodialysis patients, inflammation and malnutrition markers were associated with lower leptin and higher adiponectin levels. Additionally, high L/A ratio levels were associated with lower mortality. Further studies are needed to determine the mechanisms relating adipocytokines, inflammation and nutrition, and survival in this population.