Aims The aim is to investigate autonomic nervous system imbalance in hypertrophic cardiomyopathy (HCM) by combining echocardiographic morphological and functional parameters with the analysis of the autonomic responses to orthostatic stress. Methods A 10-min tilting test and a transthoracic echocardiogram focused on ventricular septal systolic )S wave) and diastolic function )isovolumic relaxation time) were performed. Low frequency on high frequency ratio )LF/HF) and RR variation )variation of beat to beat intervals) in response to passive orthostatism were used as measures of sympathetic reflex activation [delta LF/HF )D-LF/HF) and delta RR )DRR), respectively]. Brain natriuretic peptide was measured. Results A total of 50 HCM patients were categorized in two groups: D-LF/HF more than 0 )group 1, sympathetic response) and D-LF/HF 0 or less )group 2, parasympathetic response). Patients in group 2 had higher New York Heart Association class, a more frequent history of atrial fibrillation )38 versus 9% P=0.04) or syncope )46 versus 12% P=0.01) and an increased septal isovolumic relaxation time )122 versus 82ms P=0.02). The same categorization was made according to lowest quartile DRR )DRR at least 23 ms, group 1: sympathetic response; DRR less than 23 ms, group 2: parasympathetic response). In group 2, patients were older, with advanced New York Heart Association class and higher history of atrial fibrillation. Conclusions Autonomic response to passive orthostatism in HCM appears correlated with specific functional features of the hypertrophic heart. Altered neural afferent traffic from the localized area of segmental hypertrophy resulted in autonomic changes with a blunted sympathetic response, and an inappropriate vagal activation, especially in patients with history of atrial fibrillation or syncope.