Context: Epidemiologic data link psychological stress to adiposity. The underlying mechanisms remain uncertain. Objectives: To test whether (i) higher activity of the amygdala, a neural center involved in the response to stress, associates with greater visceral adipose tissue (VAT) volumes and (ii) this association is mediated by increased bone marrow activity. Setting: Massachusetts General Hospital, Boston, Massachusetts. Patients: Two hundred forty-six patients without active oncologic, cardiovascular, or inflammatory disease who underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging were studied. VAT imaging was repeated ;1 year later in 68 subjects. Design: Metabolic activity of the amygdala (AmygA), hematopoietic tissue activity, and adiposity volumes were measured with validated methods. Main Outcome Measure: The relationship between AmygA and baseline and follow-up VAT. Results: AmygA associated with baseline body mass index (standardized β = 0.15; P = 0.01), VAT (0.19; P = 0.002), and VAT/subcutaneous adipose tissue ratio (0.20; P = 0.002), all remaining significant after adjustment for age and sex. AmygA also associated with bone marrow activity (0.15; P = 0.01), which in turn associated with VAT (0.34; P < 0.001). Furthermore, path analysis showed that 48% of the relationship between AmygA and baseline VAT was mediated by increased bone marrow activity (P = 0.007). Moreover, AmygA associated with achieved VAT after 1 year (P = 0.02) after adjusting for age, sex, and baseline VAT. Conclusions: These results suggest a neurobiological pathway involving the amygdala and bone marrow linking psychosocial stress to adiposity in humans. Future studies should test whether targeting this mechanism attenuates adiposity and its complications.