Background In the general population, circulating adiponectin is associated with a favorable cardiovascular risk profile (eg, lower triglycerides and body fat) and decreased mortality. Hemodialysis (HD) patients have comparatively higher adiponectin concentrations, but prior studies examining the adiponectin-mortality association in this population have not accounted for body composition or shown a consistent relationship. Study Design Prospective cohort study. Settings & Participants We examined baseline serum adiponectin concentrations in 501 HD patients across 13 dialysis centers from the prospective MADRAD (Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease) cohort (entry period, October 2011 to February 2013; follow-up through August 2013). Predictor Serum adiponectin concentration in tertiles (tertiles 1, 2, and 3 defined as ≤16.1, 30.1, and ≥30.1-100.0 μg/mL, respectively). Adjustment variables included case-mix and laboratory test results (age, sex, race, ethnicity, vintage, diabetes, serum albumin, total iron-binding capacity, serum creatinine, white blood cell count, phosphate, hemoglobin, and normalized protein catabolic rate), body composition surrogates (subcutaneous, visceral, and total-body fat and lean body mass), and serum lipid levels (cholesterol, high-density lipoprotein cholesterol, and triglycerides). Outcomes All-cause mortality using survival (Cox) models incrementally adjusted for case-mix and laboratory test results. Results Among 501 HD patients, 50 deaths were observed during 631.1 person-years of follow-up. In case-mix- and laboratory-adjusted Cox analyses, the highest adiponectin tertile was associated with increased mortality versus the lowest tertile (HR, 3.35; 95% CI, 1.50-7.47). These associations were robust in analyses that additionally accounted for body composition (HR, 3.18; 95% CI, 1.61-8.24) and lipid levels (HR, 3.64; 95% CI, 1.34-7.58). Limitations Residual confounding cannot be excluded. Conclusions Higher adiponectin level is associated with a 3-fold higher death risk in HD patients independent of body composition and lipid levels. Future studies are needed to elucidate underlying mechanisms and determine therapeutic targets associated with improved outcomes in HD patients.