Ghrelin is a potent appetite stimulator, mainly synthesized in the stomach but also made in the brain. Paradoxically, obese subjects have lower plasma ghrelin than lean subjects and increase their weight in spite of low ghrelin levels. We hypothesize that central, and not peripheral ghrelin, is primarily responsible for overeating in humans. The aim of this study was to determine hypothalamic ghrelin levels in lean vs obese subjects. We collected anterior hypothalamus from lean and obese patients at the time of autopsy, and Western blots and semiquantitative RT-PCR for ghrelin and neuropeptide Y (NPY) were carried out. Our results showed that ghrelin expression was significantly higher in the hypothalamus of obese subjects compared to lean ones. This finding correlates with similar increases in NPY in the obese group. Ghrelin and NPY mRNA levels followed the same trend and were significantly higher in the hypothalamus in obese compared to lean subjects, suggesting a central origin for the increased protein content in the obese subjects. In conclusion, obesity in humans is associated with elevated central ghrelin. This data questions the significance of the role of peripheral ghrelin in the regulation of appetite in humans and suggests an important role for central ghrelin in the pathogenesis of obesity in humans.