Glucose sensing by neurons of the ventromedial hypothalamus (VMH) plays a central role in the regulation of body energy balance. Physiological rises in extracellular glucose levels hyperpolarise and inhibit a group of VMH neurons. This specialised sensing response is currently thought to involve glucose-induced activation of chloride channels, but alternative mechanisms have not been explored in detail. In this study, we converted all chloride channels from inhibitory to excitatory by filling the cytosol of VMH neurons with a high concentration of chloride. Despite this, some VMH neurons were still strongly hyperpolarised and inhibited by glucose. Voltage-clamp analysis revealed that this was due to glucose-induced activation of K(+)-selective currents of sufficient size to cause complete inhibition of whole-cell electrical activity. These K(+) currents exhibited leak-like biophysical properties and were inhibited by extracellular acidification. Our data support the idea that glucose-stimulated K(+) currents contribute to sugar-induced suppression of firing in the VMH.