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Background: Adolescents with Down syndrome (DS) are two to three times more likely to be obese than their typically developing peers. When preventing or treating obesity, it is useful for clinicians to understand an individual's energy intake needs. Predictive resting energy expenditure (REE) equations are often recommended for general use in energy intake recommendations; however, these predictive equations have not been validated in youth with DS. The aim of this study was to compare the accuracy of seven commonly used predictive equations for estimating REE in adolescents who are typically developing to REE measured by indirect calorimetry in adolescents with DS. Methods: Adolescents with DS participated in a 90‐min laboratory visit before 10:00 a.m. after a 12‐h overnight fast and a 48‐h abstention from aerobic exercise. REE was measured via indirect calorimetry, and estimated REE was derived using the Institute of Medicine, Molnar, Muller and World Health Organization equations. Mean differences between the measured and predicted REE for each equation were evaluated with equivalency testing, and P‐values were adjusted for multiple comparisons using the Holm method. Results: Forty‐six adolescents with DS (age: 15.5 ± 1.7 years, 47.8% female, 73.9% non‐Hispanic White) completed the REE assessment. Average measured REE was 1459.5 ± 267.8 kcal/day, and the Institute of Medicine equations provided the most accurate prediction of REE with a 1.7 ± 11.2% (13.9 ± 170.3 kcal/day) overestimation. This prediction was not statistically different from the measured REE [P‐value = 0.582; 95% confidence interval (CI): −64.5, 36.7], and the difference between the measured and predicted REE was statistically equivalent to zero (P‐value = 0.024; 90% CI: −56.1, 28.3). Conclusions: The results suggest that the Institute of Medicine equation may be useful in predicting REE in adolescents with DS. Future research should confirm these results in a larger sample and determine the utility of the Institute of Medicine equation for energy intake recommendations during a weight management intervention. [ABSTRACT FROM AUTHOR]