Background: Monosodium glutamate (MSG) has been shown to increase satiety when combined with protein. Inosine 5'-monophosphate acts synergistically with MSG when tasted, is present in high-protein sources, and may potentially further enhance satiety. Objective: We assessed effects of a combination of monosodium glutamate and inosine 5'-monophosphate (MSG/IMP) provided either alone or in a high-energy, high-carbohydrate and -protein soup on appetite during ingestion and postingestive satiety. Design: Fixed portions (450 g) of a low-energy control and high-energy, high-carbohydrate and -protein soup preload with added monosodium glutamate and inosine 5'-monophosphate (MSG/IMP+) or without added monosodium glutamate and inosine 5'-monophosphate (MSG/IMP-) were consumed on 4 nonconsecutive days, and changes in appetite during soup intake and at a subsequent ad libitum lunch were assessed in 26 low-restraint volunteers by using a within-participant design. Results: MSG/IMP+ conditions significantly reduced subsequent intake more than the MSG/IMP- condition did irrespective of energy. The high-carbohydrate and -protein condition also reduced intake independently of MSG/IMP. Energy compensation was greater in the MSG/IMP+ carbohydrate and protein conditions than MSG/IMP- condition. The addition of the MSG/IMP+ also increased the soup pleasantness and caused an immediate increase in appetite when the soup was first tasted. Conclusion: The addition of MSG/IMP to a low-energy preload had a biphasic effect on appetite by stimulating appetite during ingestion and enhancing postingestive satiety. This trial was registered at www.controlled-trials.com/isrctn as ISRCTN14567895.