OBJECTIVES: To determine whether autonomic dysfunction explains chronotropic incompetence observed in persons with Down syndrome (DS) and to measure heart rate variability (HRV) at rest and during exercise in persons with mental retardation with and without DS. DESIGN: Comparative study. SETTING: University exercise science laboratory. PARTICIPANTS: Thirty-one subjects with mental retardation (age, 20.2 y) with DS (n=16; 10 men, 6 women) and without DS (n=15; 8 men, 7 women). INTERVENTIONS: Not applicable. Main outcome measures HRV was determined at rest and at 2 steady-state exercise intensities on the treadmill in both time (standard deviation of the R-R interval, percentage of R-R intervals deviating by more than 50 ms from the previous R-R interval [deviation >50], square root of the mean squared differences of successive differences) and frequency (low-frequency power [LF]), high-frequency power [HF], the LF/HF ratio) domains. RESULTS: The DS group demonstrated a statistically lower peak heart rate (161 beats/min vs 178 beats/min, P<.05), and peak oxygen consumption (27.4 mL.kg(-1).min(-1) vs 34.3 mL. kg(-1).min(-1), P<.05) than did the group with mental retardation without DS. At rest, all time domain measures of HRV and absolute HF power were significantly higher in the DS group (P<.05). Yet, LF power and LF/HF values did not differ between groups. All HRV variables decreased significantly at both exercise intensities, with no differences between groups during exercise (P<.05). CONCLUSIONS: People with DS have greater parasympathetic activity at rest, but group differences disappear with the onset of exercise, which suggests that other variables are responsible for chronotropic incompetence in persons with DS.