Wilson Disease (WD) is a life-threating autosomal disorder of copper homeostasis caused by mutations in copper transporter ATP7B and characterized by toxic copper accumulation, resulting in severe and progressive liver and brain diseases. WD represents an attractive target for liver-directed gene therapy. However, classic gene replacement strategies hold limitations associated to adeno-associated viral vector (AAV) cargo capacity constraints, decline of therapeutic effect due to transgene dilution and genotoxic risk, particularly in children. We applied a liver-directed nuclease-free genome editing approach, based on AAV-mediated targeted integration of a promoterless ATP7B cDNA into the albumin locus. To this aim, we generated an AAV8 vector bearing a codon-optimized human mini-ATP7B cDNA flanked by two mouse Alb homology arms and preceded by a sequence encoding for a 2A peptide derived from porcine teschovirus-1 (AAV-Alb-mini-ATP7B). Intra-venous injection of AAV-Alb-mini-ATP7B at the dose of 2.3x1013 gc/kg in Atp7b-/- pups and adult mice resulted in a complete rescue of survival. At sacrifice, these mice showed extensive liver repopulation by genome edited hepatocytes, associated to an amelioration of liver injury and rescue of serum ceruloplasmin oxidase activity, compared to Atp7b-/- mice injected with a control vector. Furthermore, we combined promoterless nuclease-free genome editing with the administration of D-penicillamine, a copper chelator currently used for the therapy of WD. Atp7b-/- mice treated with D-penicillamine and AAV-Alb-mini-ATP7B showed a significant improvement of liver pathology and reduction of copper storage compared to Atp7b-/- mice administered with chelation therapy alone. In summary these results indicate that promoterless nuclease-free genome editing provide a significant and sustained therapeutic benefit in WD and may represent a safer alternative to classic gene replacement strategies.