People with Down syndrome (DS) have reduced gait stability and aerobic fitness that increase the metabolic rate during walking, potentially altering the relationship between metabolic rate and accelerometer output and lowering predictability of energy expenditure from accelerometry. PURPOSE: This study examined whether the relationship between metabolic rate and activity count rate differs between individuals with and without DS and whether predictability of metabolic rate is different between groups. METHODS: Metabolic rate was measured in METs with portable spirometry in 18 subjects with DS (24.7 ± 6.7 yr; 10 women) and 18 subjects without DS (26.3 ± 5.2 yr; 10 women) during five overground walking trials, each lasting 6 min, at 0.5, 0.75, 1.0, 1.25, and 1.5 m•s-1. A uniaxial accelerometer secured at the right side of the hip allowed for the determination of activity count rate. RESULTS: The relationship between METs and activity count rate in the two groups was analyzed with multilevel modeling with random intercepts and slopes, demonstrating a significant interaction between group and activity count rate (P < 0.001). Separate models for each group showed that the activity count rate and its squared significantly predicted METs (P ≤ 0.001). Actual and predicted METs did not differ in each group. Bland-Altman plots showed greater variability in the difference between actual and predicted METs for participants with DS. Mean absolute error of prediction was 19.92% and 14.55% for participants with and without DS, respectively. CONCLUSIONS: Individuals with DS show altered METs to activity count rate relationship during overground walking and have lower predictability of metabolic rate from uniaxial accelerometer output than individuals without DS. Copyright © 2011 by the American College of Sports Medicine.