Background: The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a determinant of a short-time weight regain. Thus, the objective of this study was to evaluate changes in RMR, and the associated hormonal alterations in obese patients with a very low-calorie ketogenic (VLCK)-diet induced severe body weight (BW) loss. Method: From 20 obese patients who lost 20.2 kg of BW after a 4-months VLCK-diet, blood samples and body composition analysis, determined by DXA and MF-Bioimpedance, and RMR by indirect calorimetry, were obtained on four subsequent visits: visit C-1, basal, initial fat mass (FM) and free fat mass (FFM); visit C-2, - 7.2 kg in FM, - 4. 3 kg in FFM, maximal ketosis; visit C-3, - 14.4 kg FM, - 4.5 kg FFM, low ketosis; visit C-4, - 16.5 kg FM, - 3.8 kg FFM, no ketosis. Each subject acted as his own control. Results: Despite the large BW reduction, measured RMR varied from basal visit C-1 to visit C-2, - 1.0%; visit C-3, - 2.4% and visit C-4, - 8.0%, without statistical significance. No metabolic adaptation was observed. The absent reduction in RMR was not due to increased sympathetic tone, as thyroid hormones, catecholamines, and leptin were reduced at any visit from baseline. Under regression analysis FFM, adjusted by levels of ketonic bodies, was the only predictor of the RMR changes (R-2 = 0.36; p < 0.001). Conclusion: The rapid and sustained weight and FM loss induced by VLCK-diet in obese subjects did not induce the expected reduction in RMR, probably due to the preservation of lean mass.