Background: Fatigue is a common symptom, even among healthy individuals, but little is understood about it. We examined the associations among adiposity, depressive symptoms, cytokine levels, and multidimensional fatigue symptoms in otherwise healthy subjects. Furthermore, we examined whether obesity would account for a significant portion of fatigue and, if so, what kind of fatigue complaints appear to be related to obesity. Methods: Seventy healthy subjects (36 women and 34 men) with an average age of 36.0 years and at less than or equal to 170% of ideal body weight participated in the study. Participants had their height, weight, neck circumference, ratio of the waist to hip circumference, percentage of body fat, and plasma interleukin 6 and soluble intercellular adhesion molecule 1 concentrations measured. Their sleep was monitored with an overnight polysomnogram, and subjects completed the short form of the Multidimensional Fatigue Symptom Inventory, which measures 5 domains of fatigue, and the Center for Epidemiologic Studies-Depression Scale. Results: Obesity, as measured by body mass index (calculated as weight in kilograms divided by the square of height in meters) and percentage of body fat, was associated with general fatigue. Depression scores were significantly related to all subscales of fatigue; the highest correlation was shown with emotional fatigue. The effect of obesity on physical fatigue was significant, even after controlling for depression. In general, interleukin 6 and soluble intercellular adhesion molecule-1 levels were unrelated to measures of fatigue. Conclusions: Obesity, cytokine concentrations, and depressive symptoms explained different dimensions of fatigue as measured by the short form of the Multidimensional Fatigue Symptom Inventory. Obesity accounted for a significant portion of physical fatigue after controlling for depressive symptoms and circulating levels of interleukin 6 and soluble intercellular adhesion molecule-1.