Nesfatin-1 has been described as an anorexigenic peptide. Comprehensive evidence also points towards an involvement of nesfatin-1 in the modulation of emotional pathways with a sex-specific regulation of nesfatin-1 in association with anxiety. Although the implication of nesfatin-1 in the regulation of food intake is well-established in animals, data in humans are lacking. Therefore, we investigated a possible association of circulating NUCB2/nesfatin-1 with eating disorder symptoms in female and male patients displaying a wide range of body weight. We enrolled 243 inpatients (177 female, 66 male) hospitalized due to anorexia nervosa (n = 66) or obesity (n = 144) or with normal weight and suffering from somatoform, adjustment, depressive or anxiety disorders (n = 33). Plasma samples (NUCB2/nesfatin-1 levels measured by ELISA) and measures of eating disorder symptoms (by EDI-2, range 0-100) were obtained within three days after admission. The study population displayed a distinct prevalence of eating disorder symptoms with female patients with anorexia nervosa (+ 77.0%, p < 0.001) and obesity (+ 87.9%, p < 0.001) reported significantly higher EDI-2 scores than normal weight patients of the same sex. Accordingly, males with anorexia nervosa (+ 39.7%, p < 0.05) and obesity (+ 51.7%, p < 0.001) had significantly higher EDI-2 scores than males with normal weight. Within the same BMI group, women displayed significantly higher scores than men (+ 21.4%, p < 0.05 in patients with anorexia nervosa, + 18.8%, p < 0.001 in participants with obesity). We observed a positive correlation between NUCB2/nesfatin-1 levels and EDI-2 total scores in female patients with obesity (r = 0.285, p = 0.015), whereas no associations were found in other subgroups. A positive correlation between NUCB2/nesfatin-1 levels and BMI was only observed in the male study population (r = 0.315, p = 0.018). NUCB2/nesfatin-1 plasma levels were positively associated with EDI-2 total scores in women with obesity, while no association was observable in men. The lacking association of NUCB2/nesfatin-1 and EDI-2 total scores in female patients with anorexia nervosa might be due to already low NUCB2/nesfatin-1 plasma levels. Whether NUCB2/nesfatin-1 is selectively involved in eating behavior in women with obesity will have to be further investigated.