Increased energy intakes are contributing to overweight and obesity 1,2. Growing evidence supports the role of protein appetite in driving excess intake when dietary protein is diluted (the protein leverage hypothesis) 3,4,5,6,7,8. Understanding the interactions between dietary macronutrient balance and nutrient-specific appetite systems will be required for designing dietary interventions that work with, rather than against, basic regulatory physiology. Data were collected from 26 published experimental trials measuring ad libitum intake in subjects confined to menus differing in macronutrient composition. Collectively, these trials provided variation in percent protein (spanning 8-54% of total energy), carbohydrate (1.6-72%) and fat (11-66%). These data provided an opportunity to describe the individual and interactive effects of dietary protein, carbohydrate and fat on the control of total energy intake. Percent dietary protein was negatively associated with total energy intake (F=13.4, p<0.001) irrespective of whether carbohydrate (F=0.0001, p=0.27) or fat (F=0.00, p=0.58) were the diluents of protein. The analysis strongly supports a role for protein leverage in lean, overweight and obese humans. A better appreciation of the targets and regulatory priorities for protein, carbohydrate and fat intake will inform the design of effective and health-promoting weight loss diets, food labeling policies, food production systems, and regulatory frameworks.