Background: Although mutations in the cardiac sodium and potassium channel genes are associated to the congenital long QT-syndrome (LQTS), a "modifier" role of the sympathetic nervous system was proposed to explain distinct severity of disease. We evaluated cardiac sympathetic innervation using ¹¹C-hydroxyephedrine (¹¹C-HED) and positron emission tomography (PET) in genotyped LQTS patients. Methods and Results: H₂¹⁵O and ¹¹C-HED-PET studies were performed in 11 patients (5 symptomatic) and 8 controls. Perfusion and ¹¹C-HED images were depicted as 36 sectors polar maps. Sectorial values of perfusion (H₂O%), absolute (HED_Ret) and relative (HED_%Ret) retention of ¹¹C-HED and the ratio HED_%Ret/H₂O% were calculated. Normal databases were obtained from controls. Sectorial values below 2 SD database values were defined as "outside sectors". Controls and patients showed similar sectorial perfusion. Sectorial HED_Ret did not differ between groups but means of HED_%Ret were lower in 3 sectors for patients (p<0.05). Three sectors from 3 controls had HED_%Ret below 2 SD, whereas 36 sectors in 9 patients were "outside sectors" (p<0.01). In patients average HED_%Ret/H₂O% was lower in 9 sectors (p<0.05 vs controls) and 2 "outside sectors" were found in controls but 43 in patients (p<0.01), 77% of them in the 5 symptomatic. Heterogeneous ¹¹C-HED retention was localized in septal, anterior and lateral walls. Conclusions: Most LQTS patients showed a localized and decreased pattern of ¹¹C-HED retention. Larger number of heterogeneous sectors in symptomatic patients suggests that sympathetic function could play an amplifier role for severity of the disease.