Maximal weight loss observed in low-calorie diet (LCD) studies tends to be small, and the mechanisms leading to this low treatment efficacy have not been clarified. Less-than-expected weight loss with LCDs can arise from an increase in fractional energy absorption (FEA), adaptations in energy expenditure, or incomplete patient diet adherence. We systematically reviewed studies of FEA and total energy expenditure (TEE) in obese patients undergoing weight loss with LCDs and in patients with reduced obesity (RO), respectively. This information was used to support an energy balance model that was then applied to examine patient adherence to prescribed LCD treatment programs. In the limited available literature, FEA was unchanged from baseline in short-term (<12 wk) treatment studies with LCDs; no long-term (≥26 wk) studies were found. Review of doubly labeled water and respiratory chamber studies identified 10 reports of TEE in RO patients (n = 150) with long-term weight loss. These patients, who were weight stable, had a TEE almost identical to measured or predicted values in never-obese subjects (weighted mean difference: 1.3%; range: -1.7–8.5%). Modeling of energy balance, as supported by reviewed FEA and TEE studies, suggests that obese subjects participating in LCD programs have a weight loss less than half of that predicted. The small maximal weight loss observed with LCD treatments thus is likely not due to gastrointestinal adaptations but may be attributed, by deduction, to difficulties with patient adherence or, to a lesser degree, to metabolic adaptations induced by negative energy balance that are not captured by the current models. Am J Clin Nutr 2007;85:346–54.