Severe burn induces rapid skeletal muscle proteolysis after the injury, which persists for up to 1 year and results in skeletal muscle atrophy despite dietary and rehabilitative interventions. The purpose of this research was to determine acute changes in gene expression of skeletal muscle mass regulators postburn injury. Specimens were obtained for biopsy from the vastus lateralis of a nonburned leg of eight burned subjects (6M, 2F: 34.8 ± 2.7 years: 29.9 ± 3.1% TBSA burn) at 5.1 ± 1.1 days postburn injury and from matched controls. mRNA expression of cytokines and receptors in the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) families, and the ubiquitin proteasome E3 ligases, atrogin-1 and MuRF-1, was determined. TNF receptor 1A was over 3.5-fold higher in burn. Expression of TNF-like weak inducer of apoptosis and its receptor were over 1.6 and 6.0-fold higher in burn. IL-6, IL-6 receptor, and glycoprotein 130 were elevated in burned subjects with IL-6 receptor over 13-fold higher. The level of suppressor of cytokine signaling-3 was also increased nearly 6-fold in burn. Atrogin-1 and MuRF-1 were more than 4- and 3-fold higher in burn. These results demonstrate for the first time that severe burn in humans has a remarkable impact on gene expression in skeletal muscle of a nonburned limb of genes that promote inflammation and proteolysis. Because these changes likely contribute to the acute skeletal muscle atrophy in areas not directly affected by the burn, in the future it will be important to determine the responsible systemic cues. © 2012 by the American Burn Association.