The lipase inhibitor, orlistat, is used in the treatment of obesity and reduces fat absorption by about 30%. However, the mean weight loss induced by orlistat is less than expected for the degree of fat malabsorption. It was hypothesised that lipase inhibition with orlistat attenuates the suppressive effects of oral fat on subsequent energy intake in normal-weight subjects. Fourteen healthy, lean subjects (nine males, five females; aged 25±1·3 years) were studied twice, in a double-blind fashion. The subjects received a high-fat yoghurt ‘preload’ (males 400g (2562kJ); females 300g (1923kJ)), containing orlistat (120mg) on one study day (and no orlistat on the other ‘control’ day), 30min before ad libitum access to food and drinks; energy intake was assessed during the following 8h. Blood samples were taken at regular intervals for the measurement of plasma cholecystokinin (CCK). Each subject performed a 3d faecal fat collection following each study. Energy intake during the day was greater following orlistat (10220 (sem 928) kJ) v. control (9405 (sem 824) kJ) (P=0·02). On both days plasma CCK increased (P<0·05) after the preload. Plasma CCK 20min following ingestion of the preload was less after orlistat (4·1 (sem 0·9) pmol/l) v. control (5·3) (sem 0·9) pmol/l (P=0·028); however there was no difference in the area under the curve 0–510min between the two study days. Fat excretion was greater following orlistat (1017 (sem 168) kJ) v. control (484 (sem 90) kJ) (P=0·004). In conclusion, in healthy, lean subjects the acute inhibitory effect of fat on subsequent energy intake is attenuated by orlistat and the increase in energy intake approximates the energy lost due to fat malabsorption.