End-stage renal disease associates with catabolism and sarcopenia. Hypothetically, peroral supplemental nutrition over 6months prevents catabolism in hemodialysis patients. Prospective randomized pilot study (ClinicalTrials.gov Identifier: NCT00687050). Twenty-three hemodialysis patients (15 males and 7 females) with or without human immunodeficiency virus (HIV) infection of 2 ambulatory hemodialysis centers. HIV-positive hemodialysis patients (n=7, Group 1) were started on supplemental nutrition drinks (250kcal/day), HIV-negative hemodialysis patients (n=16, Group 2) were randomized to supplemental nutrition drinks (250kcal/day) or received none. Body impedance analysis, anthropometric measures, magnetic resonance imaging results for mid-iliopsoas muscle cross-sectional area and laboratory parameters including albumin, cytokines at baseline, and at 6months follow-up. Seven patients in Group 1 (mean age: 50.6±9.6years) and 16 patients in Group 2 (mean age: 54.0±13.3years) were recruited. Serum creatinine (Group 1: 6.4±3.0mg/dL; Group 2: 10.7±2.5mg/dL; P<.01), Body impedance analysis-derived phase angle alpha (Group 1: 5.1±1.2; Group 2: 6.9±1.6; P<.01), mid-arm circumference (Group 1: 26.1±1.3cm; Group 2: 29.6±2.4cm; P<.01) were less in Group 1 versus Group 2 patients at baseline suggesting that HIV-positive hemodialysis patients had a poorer nutritional status at baseline. At 6-month follow-up, mortality was higher in Group 1 patients (29%) than in Group 2 patients (6%). There was no significant treatment effect on nutritional status in survivors of Group 1 or in the supplemental nutrition arm of Group 2 when compared with baseline or to untreated controls. A new oral supplemental nutrition over 6months had no treatment effect in surviving HIV-positive hemodialysis patients or in maintenance hemodialysis patients without HIV infection. The limitations of this study were small study size and unexpected high mortality among HIV-positive hemodialysis patients.