The hypothalamic neuropeptide orexin A (hypocretin-1) is a key signal in sleep/wake regulation and promotes food intake. We investigated the relationship between cerebrospinal fluid orexin A concentrations and body composition in non-narcoleptic human subjects with a wide range of body weight to gain insight into the role of orexin A in human metabolism. We collected cerebrospinal fluid and blood samples and measured body composition by bioelectric impedance analysis in 36 subjects (16 women and 20 men) with body mass indices between 16.24 and 38.10kg/m2 and an age range of 19–80 years. Bivariate Pearson correlations and stepwise multiple regressions were calculated to determine associations between orexin A and body composition as well as biometric variables. Concentrations of orexin A in cerebrospinal fluid averaged 315.6±6.0pg/ml, were comparable between sexes (p>0.15) and unrelated to age (p>0.66); they appeared slightly reduced in overweight/obese compared to normal-weight subjects (p=.07). Orexin A concentrations decreased with body weight (r=−0.38, p=.0229) and fat-free mass (r=−0.39, p=.0173) but were not linked to body fat mass (p>0.24). They were inversely related to total body water (r=−0.39, p=.0174) as well as intracellular (r=−0.41, p=.0139) and extracellular water (r=−0.35, p=.0341). Intracellular water was the only factor independently associated with cerebrospinal fluid orexin A concentrations (p=.0139). We conclude that cerebrospinal fluid orexin A concentrations do not display associations with body adiposity, but are inversely related to intracellular water content. These cross-sectional findings suggest a link between orexin A signaling and the regulation of water homeostasis in humans.