The effect of potato protease inhibitor II (PI2) on postprandial appetite was examined in a randomized double-blind placebo-controlled cross-over trial involving 44 healthy women. In separate test sessions, participants consumed a capsule containing placebo or potato extract standardized to 15 or 30 mg PI2 after overnight fasting. One hour later, a standard 390 kcal breakfast was served. At regular time points during the three-hour period after breakfast, appetite was measured by visual analog scales, and blood samples were collected for assay of cholecystokinin, insulin, and glucose. Compared with the placebo, consumption of 15 mg or 30 mg PI2 one hour prior to a standard breakfast meal resulted in significantly lower postprandial hunger, desire to eat, and prospective consumption, as well as significantly higher postprandial fullness. Consumption of 15 mg PI2 also resulted in significantly higher postprandial plasma levels of cholecystokinin compared with the placebo. No significant main effect of treatment was found on insulin and glucose. No adverse events were reported. Results from the study revealed that consumption of potato PI2 at the examined doses was well tolerated, suppressed subjective appetite in a dose-dependent manner, and increased plasma concentrations of cholecystokinin. Future studies are needed to evaluate the long-term effect of PI2 on body weight.