Background Lithium augmentation of antidepressants is an effective strategy in treatment-resistant depression. The proteohormone ghrelin is thought to be involved in the pathophysiology of depression. The purpose of this study was to investigate the association of treatment response with the course of ghrelin levels during lithium augmentation. Method Ghrelin serum concentrations and severity of depression were measured in 85 acute depressive patients before and after 4 weeks of lithium augmentation. Results In a linear mixed model analysis, we found a significant effect of response*time interaction (F1.81=9.48; P=.0028): under treatment, ghrelin levels increased in nonresponders and slightly decreased in responders to lithium augmentation. The covariate female gender had a significant positive effect (F1.83=4.69; P=.033), whereas time, response, appetite, and body mass index (kg/m2) did not show any significant effect on ghrelin levels (P>.05). Conclusion This is the first study showing that the course of ghrelin levels separates responders and nonresponders to lithium augmentation. Present results support the hypothesis that ghrelin serum concentrations might be involved in response to pharmacological treatment of depression.