Background When developing walking programmes for improving health in adults with Down syndrome (DS), physical activity professionals are in need of an equation for predicting energy expenditure. We therefore developed and cross‐validated an equation for predicting the rate of oxygen uptake (VO2; an index of energy expenditure) for adults with and without DS. Method A total of 469 VO2 observations during walking across different speeds were available from 54 adults with DS and 61 adults without DS. Results Significant predictors of VO2 were speed, speed square, group and group‐by‐speed interaction. Separate models for each group showed that speed and its square significantly predicted VO2. Absolute per cent error was small and did not differ between groups. Conclusion Adults with DS have different VO2 response to walking speed from persons without DS. VO2 is predicted from speed with acceptable accuracy for persons with DS.