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Changes in resting energy expenditure (EE) during weight loss are said to be greater than what can be expected from changes of body mass, i.e., fat mass (FM) and fat-free mass (FFM) but controversy persists. The primary focus of this study was to investigate whether there is a greater than predicted decrease in resting EE during weight loss in a large sample size through a systematic review. The study data were weighted and a partial residual plot followed by a multiple regression analysis was performed to determine whether FM and FFM can predict the changes of resting EE after weight loss. Another subgroup of studies from which all necessary information was available was analyzed and compared against the Harris—Benedict (HB) prediction equation to determine whether the changes in resting EE were greater than what was expected. Subjects lost 9.4 ± 5.5 kg (P < 0.01) with a mean resting EE decline of 126.4 ± 78.1 kcal/day (P < 0.01). Changes in FM and FFM explained 76.5% and 79.3% of the variance seen in absolute resting EE at baseline and post-weight loss, respectively (P < 0.01). Analysis of the 1,450 subject subgroup indicated an ∼29.1% greater than predicted decrease in resting EE when compared to the HB prediction equation (P < 0.01). This analysis does not support the notion of a greater than predicted decrease in resting EE after weight loss.