Arrhythmogenic Cardiomyopathy (AC) is a genetic cardiac disease, mainly associated to mutations in desmosomal proteins, featuring cardiomyocyte death and myocardial fibro-fatty replacement, which lead to contractile dysfunction and favour stress-induced, life-threating arrhythmias. In fact, AC accounts for most sudden cardiac deaths (SCD) in young and athletes, and the incomplete understanding of disease mechanisms results in the absence of efficacious preventive therapies. Correlation between SCD and physical/emotional stresses incriminates sympathetic neurons (SNs) of triggering arrhythmias, but if SNs are also implicated in structural heart remodeling is unexplored. Interestingly, current literature and our data show that desmosomal proteins are expressed by SNs, which harbour AC-linked mutations, and may thus be additional cell types involved in AC pathogenesis. Here, we analyzed hearts of two AC mouse models, generated by us, the former harboring a mutation in Desmoglein-2 (Dsg2mut/mut) and the latter, in Desmoplakin (DSPS311A), both with ubiquitous expression of the transgenes. Cardiac sympathetic innervation, analyzed in Dsg2mut/mut mice showed globally increased SN density, with enhanced axonal sprouting, irregular morphology and distribution of varicosities. In DSPS311A/S311A mice, hyper-innervated and denervated myocardial areas coexist. Notably, in both strains, SN density was highest close to the remodeled myocardial areas, as shown by multiphoton microscopy of clarified hearts. These findings were confirmed in autoptic heart samples from DSP and DSG2 AC patients. Remarkably, alterations in mouse heart innervation started before myocardial remodelling was detectable, suggesting that abnormal cardiac innervation may be an independent event, preceding and participating to myocardial remodelling, and that SNs are directly affected by AC-mutations. This was confirmed by in vitro assays on cSNs from neonatal mice. Our results indicate that SNs are additional cell types affected in AC, and that altered sympathetic innervation in AC hearts results from the combination of genotype-dependent, cell-autonomous and context dependent factors.