Estimations based on the available equations for predicting oxygen uptake (V̇o ) from treadmill speed of locomotion are not appropriate for individuals with Down syndrome (DS). We aimed at developing prediction models for peak absolute oxygen uptake (V̇o ) and peak heart rate (HR ) based on retrospective data from a healthy population with and without Down syndrome (DS). A cross-sectional analysis of V̇o and HR was conducted in 196 and 187 persons with and without DS, respectively, aged from 16 to 45 yr. Nonexercise data alone versus combined with HR were used to develop equations predictive of absolute V̇o . Prediction equations for HR were also developed. Two additional samples of participants (30 with, 29 without DS) enabled model cross-validation. Relative V̇o and HR were lowest for persons with DS across all ages (∼40% and 20 beats·min , respectively). For persons with DS, V̇o predictions provided no differences compared with actual values. Predicted HR was similar to actual values in both groups of participants. Large limits of agreement were obtained for V̇o (DS: 735, non-DS: 558.2 mL·min ) and HR (DS: 24.8, non-DS: 16.6 beats·min ). Persons with DS exhibit low levels of V̇o and HR in all age groups included in this study. It is possible to estimate absolute V̇o in persons with DS using nonexercise variables. HR can be accurately estimated in groups of people with and without DS. Yet, because of large limits of agreement, caution is advised if using these equations for individual estimations of V̇o or HR in either population. Our data show that it is possible to estimate absolute peak oxygen uptake in persons with Down syndrome using nonexercise variables. Peak heart rate can also be accurately estimated in groups of people with and without Down syndrome. However, because of large limits of agreement, caution is advised if using these equations for individual estimations of peak oxygen uptake or peak heart rate in either population.