Background: Persons with Down syndrome (DS) have low aerobic exercise capacity. The present authors sought to compare the oxygen uptake efficiency slope (OUES) between adults with and without DS performing graded exercise testing (GXT) and to investigate its relationship with peak oxygen uptake (VO[subscript 2peak]) in both groups of participants. Method: Twenty-three participants with DS and 24 non-disabled controls performed GXT with VO[subscript 2] measurements. OUES was calculated from data of the first 75%, 90% and 100% GXT time. Multiple linear regression analyses were computed to explore associations between the independent (OUES and DS) and the dependent variables (VO[subscript 2peak]). Results: VO[subscript 2peak], GXT time and OUES were lower in participants with DS (p < 0.05). OUES and DS explained 69.3% of the variance in VO[subscript 2peak]. Conclusions: Our findings show that OUES values are lower in persons with DS. Additionally, it was shown that OUES has predictive value for VO[subscript 2peak] estimations in DS.