Decreased dietary protein intake and hemodialysis (HD)-associated protein catabolism predispose chronic HD (CHD) patients to deranged nutritional status, which is associated with poor clinical outcome in this population. Intradialytic parenteral nutrition (IDPN) reverses the net negative whole-body and skeletal muscle protein balance during HD. IDPN is costly and restricted by Medicare and other payers. Oral supplementation (PO) is a more promising, physiologic, and affordable intervention in CHD patients. Protein turnover studies were performed by primed-constant infusion of l-(1-13C) leucine and l-(ring-2H5) phenylalanine in eight CHD patients with deranged nutritional status before, during, and after HD on three separate occasions: (1) with IDPN infusion, (2) with PO administration, and (3) with no intervention (control). Results showed highly positive whole-body net balance during HD for both IDPN and PO (4.43 ± 0.7 and 5.71 ± 1.2 mg/kg fat-free mass per min, respectively), compared with a neutral balance with control (0.25 ± 0.5 mg/kg fat-free mass per min; P = 0.002 and <0.001 for IDPN versus control and PO versus control, respectively). Skeletal muscle protein homeostasis during HD also improved with both IDPN and PO (50 ± 19 and 42 ± 17 μg/100 ml per min) versus control (−27 ± 13 μg/100 ml per min; P = 0.005 and 0.009 for IDPN versus control and PO versus control, respectively). PO resulted in persistent anabolic benefits in the post-HD phase for muscle protein metabolism, when anabolic benefits of IDPN dissipated (−53 ± 25 μg/100 ml per min for control, 47 ± 41 μg/100 ml per min for PO [P = 0.039 versus control], and −53 ± 24 μg/100 ml per min for IDPN [P = 1.000 versus control and 0.039 versus PO]). Long-term studies using intradialytic oral supplementation are needed for CHD patients with deranged nutritional status.