The resting membrane potential difference (Em) of skeletal muscle was measured in 26 normal human subjects, 7 patients with mild illness, and 21 patients with severe, debilitating medical disorders. A closed transcutaneous approach to the muscle was made by needle puncture and the Em was measured utilizing standard Ling electrodes. Measurements revealed an Em of -88 ±-3.8 mv in healthy subjects and -89 ± 2.1 mv in patients hospitalized for minor medical problems. The mean Em in 21 in-hospital patients, judged to be severely ill clinically from a variety of causes, was -66.3 ±9.0 mv. Open deltoid muscle biopsies were performed in 7 of the healthy subjects and in 13 of the severely ill group. Estimation of the intraextracellular water partition was made by calculating the chloride space from the previously measured Em. Analysis of the muscle samples revealed no significant difference in the intra-extracellular potassium ratios of the two groups biopsied. Intracellular Nat concentrations were uniformly increased in the muscle samples of the severely ill subjects and averaged 42.3% higher than those of the normal subjects. The mechanisms which might account for the elevation of intracellular Nat and a depression of Em independent of changes in intraextracellular Ki' ratios are discussed and it is suggested that this defect may be a generalized cellular abnormality which is a common quality of serious illnesses.