To understand how and why sleep deprivation is physically harmful, we explored the possible causal relationship between its two main effects, 1) negative energy balance and 2) a composite of symptoms that resemble protein malnutrition, both of which occur despite increased food consumption. We provided balanced diets augmented with either protein or calories (by increased fat content) to freely moving rats. Interactions between sleep deprivation symptoms and energy and protein supplies were assessed from measurements of body weight regulation, consumption of macronutrients, clinical chemistry and hematology profiles, and physical appearance. The results indicate that sleep deprivation causes malnutrition, which is secondary to increased energy expenditure. Even though food consumption remained normal in sleep-deprived rats fed a diet of high protein-to-calorie ratio, body weight loss was more than 16% of baseline, development of skin lesions was hastened, and longevity was shortened by 40% compared with sleep-deprived rats fed the calorie-augmented diet. Food consumption of the calorie-fed rats was lower during baseline than that of the protein-fed group but during sleep deprivation increased to amounts 250% of normal without net body weight gain. Despite a fat-laden diet the calorie-fed hyperphagic group did not have abnormal levels of plasma cholesterol, triglycerides, or glucose, indicating accelerated turnover of nutrients. As would be consistent with calorie malnutrition, pronounced clinical chemistry or hematological abnormalities were not found in any group. Beneficial effects of the calorie-augmented diet are attributed to 1) caloric density of fat, 2) induction of hyperphagia, and 3) efficiency of utilization of fat. We conclude that diet composition interacts strongly with sleep deprivation, affecting the time course and development of pathologies, whereas it exerted negligible influence on body weight regulation under normal conditions.