People with Down syndrome (DS) show altered autonomic response to sympatho-excitation. Cardiac autonomic modulation may be examined with heart rate (HR) complexity which is associated uniquely with cardiovascular risk. This study examined whether the response of HR complexity to passive upright tilt differs between persons with and without DS and whether potential between-group differences in this response are accounted for by differences in body mass index (BMI). The electrocardiogram of 16 persons with DS (8 women, 8 men) and 16 persons without DS (8 women, 8 men) was recorded during 10 min of supine rest and 10 min of upright tilt. For each participant, 550 continuous, steady state, and ectopy-free R-R intervals under each condition were analyzed. Dependent variables were approximate entropy, correlation dimension, StatAv, and the mean R-R interval. In response to tilt, changes in approximate entropy and correlation dimension were reduced in participants with DS (p less than 0.05). These differences were explained by higher BMI in participants with DS. StatAv increased in persons with DS (p less than 0.05) and stayed the same in those without DS even when controlling for BMI. The response of R-R interval did not differ between groups. None of the variables differed between groups at rest. Therefore, people with DS show smaller decrease in HR complexity in response to upright tilt than people without DS partially due to their higher BMI. Resting HR complexity does not differ between persons with and without DS. These results may have implications for cardiovascular risk in people with DS. (Contains 1 figure.)