To assess the relationship between regional myocardial perfusion and sympathetic innervation parameters at myocardial scintigraphy and intra-cavitary electrophysiological data in patients with ventricular arrhythmias (VA) submitted to invasive electrophysiological study and ablation procedure. Sixteen subjects underwent invasive electrophysiological study with electroanatomical mapping (EAM) followed by trans-catheter ablations of VA. Before ablation all patients were studied with a combined evaluation of regional myocardial perfusion and sympathetic innervation by means of tomographic 99mTc-tetrofosmin and 123I- metaiodobenzylguanidine cadmium-zinc-telluride (CZT) scintigraphies, respectively. Off-line spatial co-registration of CZT perfusion and innervation data with the three-dimensional EAM reconstruction was performed in every patient. CZT revealed the presence of myocardial scar in 55 (20 %) segments. Of the viable myocardial segments, 131 (60 %) presented a preserved adrenergic innervation, while 86 (40 %) showed a significantly depressed innervation (i.e. innervation/perfusion mismatch). On EAM, the invasively measured intra-cavitary voltage was significantly lower in scarred segments than in viable ones (1.7 ± 1.5 mV vs. 4.0 ± 2.2 mV, P < 0.001). Interestingly, among the viable segments, those showing an innervation/perfusion mismatch presented a significantly lower intra-cavitary voltage than those with preserved innervation (1.9 ± 2.5 mV vs. 4.7 ± 2.3 mV, P < 0.001). Intra-cardiac ablation was performed in 63 (23 %) segments. On multivariate analysis, after correction for scar burden, the segments showing an innervation/perfusion mismatch remained the most frequent ablation targets (OR 5.6, 95 % CI 1.5–20.8; P = 0.009). In patients with VA, intra-cavitary electrical abnormalities frequently originate at the level of viable myocardial segments with depressed sympathetic innervation that frequently represents the ultimate ablation target.