Depression has been linked to altered cardiac autonomic regulation. Previous studies have been inconsistent in terms of measurement of heart rate variability (HRV), selection of depressed patients with cardiac disorders and not controlling for co-morbid conditions such as substance use and anxiety disorders. The objective of this study is to compare the effect of posture on spectral measures of HRV in drug naive healthy patients with major depression with age and gender matched healthy controls. Spectral measures of HRV in supine position and with active standing were obtained (using Task force recommendations). Repeated measure ANOVA revealed an attenuated response in HRV parameters (HF normalized units & LH/HF ratio) to active standing in depressed subjects compared to healthy controls. We conclude that there is an impaired parasympathetic modulation in response to physiological maneuver (orthostatic challenge) in drug naive subjects with major depression (co-morbid medical or psychiatric conditions) compared to healthy controls.