OBJECTIVE: This study explored whether the increased extracellular relative to intracellular fluid (ECF/ICF) ratio in obesity mightreflect osmotic effects of elevated plasma solute concentrations. DESIGN: Cross-sectional, epidemiological survey. SETTING AND SUBJECTS: The present analysis used nationally representative data from the Third National Health and Nutrition Examination Survey on community-dwelling adults (aged 40-59 years) in the US without evidence of glucose dysregulation or chronic disease (n=1285). INTERVENTION: Body mass index (BMI) was estimated from measured height and weight. Total body reactance, an index of bodyfluid distribution, was determined by bioelectrical impedance analysis. Plasma tonicity (the cumulative index of osmotically effectiveplasma solute) was estimated from plasma glucose, sodium and potassium. Sex-specific relative odds of lower reactance (<or=50 Omega/m for women, <or=40 Omega/m for men) and plasma hypertonicity (tonicity >or=295 mmol/l) associated with overweight (25<or=BMI <30) and obesity (BMI>or=30) were estimated using logistic regression models that controlled for sociodemographic variables, smoking, leisure-time physical activity, total energy intake, serum creatinine, plasma insulin and glucose. Multinomial logistic regression models tested for associations between weight status and specific serum solute. RESULTS: Independent of covariates, in men and women, overweight and obesity were associated with increased odds of lower reactance and hypertonicity. Overweight and obese individuals with lower reactance had significantly higher serum sodium than normal weight individuals. CONCLUSIONS: Elevated plasma solute concentrations are associated with obesity in free-living adults. Physicians and researchers should be alert to a possible link between hypertonicity and obesity. SPONSORSHIP: Grants from the NIH, Nestle Waters.