Using a double-blind, placebo-controlled crossover design, the effects of 48 h near complete energy restriction on endocrine regulators of appetite and satiety were assessed. Twelve men and one woman participated in this controlled, 2-day diet intervention study. One experimental trial was completed in a calorie deprived state (CAL-DEP; <10% of estimated energy requirements) and others in a fed condition (carbohydrate only and carbohydrate and fat; data were pooled and compared to CAL-DEP). Test meals containing prescribed energy intake and indistinguishable in sensory characteristics were provided during each trial. Glucose, insulin, leptin, ghrelin, cortisol, dehydroepiandrosterone-sulfate (DHEA-S), and satiety were repeatedly assessed. Mean glucose, insulin, and leptin concentrations were lower (P < 0.0001) for CAL-DEP compared to the fully fed (FED) state. Ghrelin and DHEA-S were higher (P < 0.0001) for CAL-DEP relative to FED. Cortisol levels declined each day regardless of diet (P < 0.0001) but were 32% higher (P < 0.01) at the conclusion of the session for CAL-DEP compared to FED. Satiety was 25% lower (P < 0.0001) for CAL-DEP relative to FED and decreased (P < 0.0001) over time regardless of diet. In the FED state, insulin (r = 0.55), glucose (r = 0.76), cortisol (r = -0.59), and DHEA-S (r = -0.62) were associated (P < 0.05) with satiety, but not during CAL-DEP. These findings show that 2 days of severe energy restriction alter several endocrine regulators of appetite independent of perception of increased hunger suggesting a physiological mechanism to explain overeating following acute periods of severe energy restriction.