© 2020 University of Alabama at Birmingham. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS) Objective: The aim of this study was to investigate whether baseline (pre–weight loss) metabolic variables can predict weight regain. Methods: About 117 women with overweight completed a weight loss program to achieve BMI < 25 kg/m2 and were followed for 2 years. Resting metabolic rate, respiratory quotient, insulin sensitivity, and serum leptin concentration were measured pre–weight loss, while on energy balance, and as predictors of weight regain at 1 and 2 years. Rate and amount of weight loss also were examined as predictors, as these outcomes may reflect metabolic phenotype. Results: Average weight loss was 12 (SD 2.5) kg, and regain was 48% (SD 35%) and 80% (SD 52%) at 1 and 2 years, respectively. In regression modeling, metabolic variables (both pre–weight loss and changes with weight loss) did not predict weight regain. However, initial weight loss and time to achieve BMI < 25 were significant predictors of weight regain at 1 and 2 years, even after adjusting for confounders. Conclusions: Baseline (pre–weight loss) resting metabolic rate, respiratory quotient, insulin sensitivity, and leptin did not predict weight regain. However, a larger and faster weight loss was associated with a lower weight regain. Understanding the mechanisms behind interindividual variation in magnitude and rate of weight loss is needed to ensure better weight loss maintenance.