In addition to its anorexigenic properties in the neuroendocrine regulation of hunger and satiety, mounting evidence indicates a role for NUCB2/nesfatin-1 in the regulation of emotional stress responses which seems to occur in a sex-specific way. In the present study, we investigated the association of NUCB2/nesfatin-1 plasma levels with anxiety, depressiveness and perceived stress in obese men and women and their alterations during inpatient treatment. We expected a decrease of NUCB2/nesfatin-1 levels in female and an increase in male patients reporting a relevant alleviation of anxiety. We analyzed 69 inpatients (44 female, 25 male; body mass index, mean: 50.2±9.5kg/m2, range: 31.8-76.5kg/m2; mean age: 45.0±12.4years) hospitalized due to morbid obesity with mental (not necessarily anxiety disorders) and somatic comorbidities. NUCB2/nesfatin-1 plasma levels were measured by ELISA. Anxiety (GAD-7), depressiveness (PHQ-9) and perceived stress (PSQ-20) were concurrently determined as patient-reported outcomes. All measurements were carried out at the initiation of and during inpatient treatment when a clinically meaningful improvement of anxiety was achieved (≥5 points on GAD-7) or missed (±1 point). NUCB2/nesfatin-1 was positively correlated with anxiety scores in women at the beginning of (r=0.411; p=0.006) and during (r=0.301; p=0.047) inpatient treatment. In men, a significant negative correlation was observed following treatment (r=-0.469; p=0.018), while at the outset of treatment only a trend was observed (r=-0.381; p=0.059). Unexpectedly, neither women (n=19; at beginning vs. during treatment; 0.49±1.00ng/ml vs. 0.38±0.72ng/ml; p=0.687) nor men (n=9; 0.17±0.31ng/ml vs. 0.19±0.36ng/ml; p=0.427) who improved in anxiety scores (p<0.001) displayed significant changes of NUCB2/nesfatin-1 plasma levels, although the direction of change was as expected with a decrease in women (-23.3%) and an increase in men (+12.4%). In addition, the change of NUCB2/nesfatin-1 was not explained by the course of anxiety (women: p=0.587; men: p=0.373). In conclusion, women and men showed an inverse association between NUCB2/nesfatin-1 and anxiety with a positive correlation in women and a negative correlation in men (although this correlation was not statistically significant in men at the beginning of treatment). However, no significant change of NUCB2/nesfatin-1 following improvement of anxiety has been observed. This might be due to the short observation interval, or due to too small anxiety improvements associated with too low baseline anxiety levels.