In recent years, clear evidence has accumulated that insulin affects central nervous functions. Besides controlling metabolic processes such as energy homeostasis by the regulation of food intake through hypothalamic receptors, the peptide hormone also appears to be capable of modulating cognitive functions. Experimental and clinical evidence for insulin supports effects on learning and memory. This study explores the impact of insulin on neuronal activity using a picture encoding task in a functional magnetic resonance imaging approach. Ten subjects performed two independent scanning sessions, each session divided into one part of four baseline runs and a second part of four runs during either insulin or saline was infused. A hyperinsulinemic-euglycemic clamp technique was applied to keep the blood glucose concentrations normal during insulin infusion. Contrast images between the two parts revealed identical activation patterns during baseline and saline conditions while during the insulin condition a higher level of activation was detected within the fusiform gyrus in both hemispheres. Shorter reaction times during the insulin condition underlined the cognitive benefit. For the first time, we were able to demonstrate that insulin enhances neuronal activity within the medio-temporal lobe and increased performance in humans under in-vivo conditions.