The concept of SEEKING describes a predisposition to search enthusiastically for rewards in the environment. While SEEKING and its underlying functional anatomy have been extensively investigated in animals, such processes in humans, especially brain-damaged individuals, remain understudied. We therefore conducted an exploratory behavioral study in stroke patients to investigate the effects of brain lesions that anatomically could be interpreted to impact the SEEKING system and predicted relationships to depression. Patients with lesions in anterior, medial, and/or subcortical lesions showed significantly lower SEEKING scores and higher depression scores than nonlesioned subjects in the control group. Based on our data and related work on animals, we propose central involvement of the anterior subcortical-cortical midline system as core of the limbic system in SEEKING in humans.